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Information on EC 2.7.1.91 - sphingosine kinase
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2.7.1.91 sphingosine kinaseIUBMB Comments
The enzyme is involved in the production of sphingolipid metabolites. It phosphorylates various sphingoid long-chain bases, such as sphingosine, D-erythro-dihydrosphingosine (sphinganine), phytosphingosine (4-hydroxysphinganine), 4-hydroxy-8-sphingenine, 4,8-sphingadienine and D-threo-dihydrosphingosine and L-threo-dihydrosphingosine. The exact substrate range depends on the species.
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Word Map
- 2.7.1.91
- sphingosine-1-phosphate
- 1-phosphate
- sphingolipids
- ceramide
- endothelial
- sirnas
- necrosis
- agonist
- metastasis
- artery
- erk
- phospholipase
- fingolimod
- fibrosis
- lymphocyte
-
protein-coupled
- sphingomyelinase
- tnf
- pulmonary
- leukemia
- sphingomyelin
-
anti-apoptotic
-
s1p-induced
- stat3
- pertussis
- mapks
-
pro-apoptotic
-
mitogen
- sclerosis
- pkc
-
rheostat
-
signal-regulated
- caspase-3
-
pro-survival
-
platelet-derived
- lysophospholipids
-
cardioprotective
- phytosphingosine
- drug development
- lymphopenia
-
egress
- glucosylceramide
- medicine
- fumonisins
-
s1p-mediated
- dihydroceramide
-
mitogenesis
-
pdgf-induced
-
ceramide-induced
-
lysophosphatidic
- fcepsilonri
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
sphk1, sphingosine kinase, sphk2, sphingosine kinase 1, sphingosine kinase-1, sphingosine kinase 2, sphk-1, sphingosine kinase-2, sphk1a, sphingosine kinase type 1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dihydrosphingosine kinase
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-
-
-
kinase, dihydrosphingosine (phosphorylating)
-
-
-
-
kinase, sphingosine (phosphorylating)
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-
-
-
SK
SK-1
SK-2
SK1
SK2
sphinganine kinase
sphingoid base kinase
-
-
-
-
sphingosine kinase
sphingosine kinase 1
sphingosine kinase 2
sphingosine kinase-1
sphingosine kinase-2
SPHK
SPHK-1
SPHK1
SPHK2
additional information
SK
-
-
-
-
sphinganine kinase
-
sphingosine kinase 1
-
sphingosine kinase 2
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sphingosine kinase-1
is a substrate for the cysteine protease cathepsin B
sphingosine kinase-1
is a substrate for the cysteine protease cathepsin B
sphingosine kinase-1
is a substrate for the cysteine protease cathepsin B
SPHK
-
-
-
-
SPHK1
-
additional information
-
the enzyme belongs to the subfamily of diacylglyceride kinases DAGKs
additional information
-
the enzyme belongs to the subfamily of diacylglyceride kinases DAGKs
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
-
-
-
-
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
overview on regulation
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
overview on regulation
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
Asp177 in C4 domain of isozyme SK1a is important for sphingosine substrate recognition
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism, the catalytic domain contains the C1-C5 sequence stretches and the ATP-binding site
-
ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
catalytic mechanism, the catalytic domain contains the C1-C5 sequence stretches and the ATP-binding site
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ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate
Lys103 is important in catalysis
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
ATP:sphingoid base 1-phosphotransferase
The enzyme is involved in the production of sphingolipid metabolites. It phosphorylates various sphingoid long-chain bases, such as sphingosine, D-erythro-dihydrosphingosine (sphinganine), phytosphingosine (4-hydroxysphinganine), 4-hydroxy-8-sphingenine, 4,8-sphingadienine and D-threo-dihydrosphingosine and L-threo-dihydrosphingosine. The exact substrate range depends on the species.
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CAS REGISTRY NUMBER
COMMENTARY
50864-48-7
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
ATP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutan-1-ol
ADP + (2R)-2-amino-4-(4-heptoxyphenyl)-2-methylbutyl dihydrogen phosphate
-
isoform SPHK2 is 6fold more efficient than SPHK1 in phosphorylating
product is a nanomolar agonist of sphingosine 1-phsphate receptor 1, whereas the (2S)-enantiomer is much weaker
-
?
ATP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol
ADP + (2R,3R)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-yl dihydrogen phosphate
-
no substrate for SPHK1, phosphorylated by SPHK2 at low rates
product is a potent agonist of sphingosine 1-phsphate receptor 1
-
?
ATP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol
ADP + 1-O-hexadecyl-2-deoxy-2-amino-sn-glycerol 3-phosphate
-
isozyme SPHK2, 10fold lower activity with isozyme SPHK1
-
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
ATP + 4,8-sphingadienine
ADP + 4,8-sphingadienine 1-phosphate
-
high activity
-
-
ir
ATP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine
ADP + 7-nitro-2-1,3-benzoxadiazol-4-yl-labeled sphingosine 1-phosphate
-
-
-
?
ATP + biotinyl-D-erythro-sphingosine
ADP + biotinyl-D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-dihydrosphingosine
ADP + D-erythro-dihydrosphingosine 1-phosphate
the activity of longrSK1 towards dihydrosphingosine is about 3.6fold higher than that of rSK1
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-
?
ATP + DELTA4-unsaturated long chain sphingosine
ADP + DELTA4-unsaturated long chain sphingosine 1-phosphate
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high activity
-
-
ir
ATP + DL-erythro-dihydrosphingosine
ADP + DL-erythro-dihydrosphingosine 1-phosphate
-
-
-
?
ATP + fluorescein-labeled sphingosine
ADP + fluorescein-labeled sphingosine 1-phosphate
-
-
-
-
?
ATP + L-(-)-threo-sphinganine
ADP + L-(-)-threo-sphinganine 1-phosphate
-
-
-
-
?
ATP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine
ADP + N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-6-aminocaproyl-D-erythro-sphingosine 1-phosphate
-
-
-
-
?
ATP + sphingosine-fluorescin
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
-
approximately 20% the activity of sphingosine at isoformSPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol
ADP + (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propyl dihydrogen phosphate
-
-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
-
good substrate of isoform SPHK2
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propan-1-ol
ADP + 2-amino-2-[4-(4-octylphenyl)-1,3-oxazol-2-yl]propyl dihydrogen phosphate
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-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
-
moderate activity at isoform SPHK2, it is the only alcohol in the series to have significant activity at isoform SPHK1
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propan-1-ol
ADP + 2-amino-2-[5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl]propyl dihydrogen phosphate
-
-
product is a sphingosine 1-phosphate receptor prodrug
-
?
ATP + D-(+)-erythro-sphinganine
ADP + D-(+)-erythro-sphinganine 1-phosphate
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-
-
-
?
ATP + D-(+)-erythro-sphinganine
ADP + D-(+)-erythro-sphinganine 1-phosphate
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-
-
?
ATP + D-(+)-erythro-sphinganine
ADP + D-(+)-erythro-sphinganine 1-phosphate
-
-
-
-
?
ATP + D-(+)-erythro-sphinganine
ADP + D-(+)-erythro-sphinganine 1-phosphate
-
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
nucleotide binding in the cleft between the N-terminal domain and C-terminal domain
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?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
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major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
-
-
-
?
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
C14 and C16 dihydrosphingosine substrates
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
-
-
-
?
ATP + DL-threo-dihydrosphingosine
ADP + DL-threo-dihydrosphingosine 1-phosphate
-
isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
immunomodulatory drug, high activity with isozyme SPHK2, 7fold lower activity with isozyme SPHK1
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
-
FTY720 is stereoselectively phosphorylated to the active principle (S)-FTY720-phosphate which binds to four of the five known sphingosine-1-phosphate receptors. The introduction of a second stereocenter in the amino alcohol head group of FTY720-like compounds has a strong effect on the phosphorylation efficiency and selectivity by SPHKs and on transiently decreasing peripheral lymphocyte counts in vivo
-
-
?
ATP + FTY720
ADP + FTY720 1-phosphate
immunomodulatory drug, high activity with isozyme SPHK2, lower activity with isozyme SPHK1
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
-
phytosphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
-
i.e. 4-hydroxysphinganine, moderate or low activity
-
-
ir
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
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isozyme SPHK2, no activity with isozyme SPHK1
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
i.e. dihydrosphingosine, moderate or low activity
-
-
ir
ATP + sphinganine
ADP + sphinganine 1-phosphate
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involved in signal transduction in the nucleus
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
2fold higher activity with isozyme SPHK1 compared to isozyme SPHK2
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
SK2 has a higher substrate affinity to sphinganine than to sphingosine
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
overview on cellular functions
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
involved in regulation of GTP cyclohydrolase I and 6(r)-5,6,7,8-tetrahydrobiopterin
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
D-erythro-sphinganine, sphingosine metabolism
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
calcium mobilization through antigen receptors utilizes enzyme
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
overview on cellular functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
C14 and C16 sphingosine substrates
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
short-living product S1P is a bioactive lipid mediator in diverse cellular processes, e.g. regulation of cell differentiation, motility, and apoptosis both extracellularly via S1P family receptors and intracellularly
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
involved in diverse biological functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
isozymes SPHK1 is about 100fold more active than isozyme SPHK2
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
additional information
?
-
-
substrate specificity of cytosolic and membrane enzymes, 4-hydroxy-8-sphingenine is a poor substrate
-
-
?
additional information
?
-
-
sphingosine 1-phosphate is responsible for resistance to the anticancer drug cisplatin
-
-
?
additional information
?
-
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
?
additional information
?
-
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
?
additional information
?
-
-
FYT720 is no substrate of isozymes SphK1 and SphK2
-
-
?
additional information
?
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
isozyme SK1 shows high activity compared to isozyme SK2, development and optimization of a high-sensitive assay method utilizing biotinyl sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
isozyme SK2 shows low activity compared to isozyme SK1, development and optimization of a high-sensitive assay method utilizing biotinyl-sphingosine and streptavidin-coated membranes with recombinant isozymes
-
-
?
additional information
?
-
-
no activity with ceramide, the 2 isozymes interact with a number of proteins, overview
-
-
?
additional information
?
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
?
additional information
?
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
-
use of an automated single-cell capillary electrophoresis system to characterize the sphingosine-1-phosphate pathway in single primary human NK cells from peripheral blood, method development, overview. The automated single-cell CE system increases throughput 100fold compared to that attained by non-automated systems, permitting the analysis of sufficiently large sample sizes to identify statistically significant differences of sphingosine-1-phosphate pathway signaling
-
-
?
additional information
?
-
-
sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis
-
-
?
additional information
?
-
-
sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering migration of dendritic cells
-
-
?
additional information
?
-
shows no activity towards DL-threo-dihydrosphingosine, dimethylsphingosine, C2-ceramide, dioleoylacylglycerol, or phosphatidylserine
-
-
?
additional information
?
-
long-rSK1 is involved in cell signaling
-
-
?
additional information
?
-
no phosphorylation of with threo-dihydrosphingosine, N,N-dimethylsphingosine and N-acetyl-D-sphingosine
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + dihydrosphingosine
ADP + dihydrosphingosine 1-phosphate
C14 and C16 dihydrosphingosine substrates
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
major substrate of isozyme SPHK1, also active with isozyme SPHK2
-
-
?
ATP + D-erythro-sphingosine
ADP + D-erythro-sphingosine 1-phosphate
-
-
-
?
ATP + phytosphingosine
ADP + phytosphingosine 1-phosphate
-
phytosphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
involved in signal transduction in the nucleus
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, acts often in concert with ceramide 1-phosphate, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
overview on cellular functions
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
involved in regulation of GTP cyclohydrolase I and 6(r)-5,6,7,8-tetrahydrobiopterin
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
the lipid phosphate acts as a pleiotropic agent in cell signalling pathways, enzyme is involved in the sphingomyelid pathway, overview
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
D-erythro-sphinganine, sphingosine metabolism
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
calcium mobilization through antigen receptors utilizes enzyme
-
-
?
ATP + sphinganine
ADP + sphinganine 1-phosphate
-
overview on cellular functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine 1-phosphate is capable of regulating the turgor in guard cells/stomatal aperture via G-proteins
-
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
C14 and C16 sphingosine substrates
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a mediator in diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
sphingosine is a modulator of membrane signal transduction systems and a regulatory element of cardiac and skeletal muscle physiology
sphingosine 1-phosphate is a intracellular messenger molecule and ann extracellular ligand for specific membrane receptors
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
short-living product S1P is a bioactive lipid mediator in diverse cellular processes, e.g. regulation of cell differentiation, motility, and apoptosis both extracellularly via S1P family receptors and intracellularly
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
involved in diverse biological functions
-
-
?
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
ATP + sphingosine
ADP + sphingosine 1-phosphate
-
-
sphingosine 1-phosphate is a potent bioactive sphingolipid, sphingolipid metabolism, overview
-
ir
additional information
?
-
-
sphingosine 1-phosphate is responsible for resistance to the anticancer drug cisplatin
-
-
?
additional information
?
-
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
?
additional information
?
-
requirement for Sk2 in normal reproductive function, product S1P signaling promotes cell proliferation, survival, and migration, enzyme reduces cellular levels of sphingosine and ceramide, sphingolipid metabolism, overview
-
-
?
additional information
?
-
-
isozyme SPHK1 is involved in responses to macrophages, the enzyme is involved in mast cell signalling, in neutrophil priming, and in prostaglandin biosynthesis via arachidonic acid production, overview, sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
sphingosine and sphingosine 1-phosphate activate phospholipase D in mouse myoblasts
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation and via neutrophil, macrophage, and monocyte activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis, chemotaxis of leukocytes
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
-
-
?
additional information
?
-
-
sphinganine 1-phosphate acts as an extracellular mediator by binding to specific members of the EDG-family of G-protein coupled receptors, and intracellularly as a messenger
-
-
?
additional information
?
-
-
the enzyme is involved in many cellular processes, e.g. mast cell activation during inflammation, immunoactivation via intracellular Ca2+ and receptor activation, angiogenesis and control of cell adhesion molecule expression, anti-apoptosis
-
-
?
additional information
?
-
-
sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering migration of dendritic cells
-
-
?
additional information
?
-
long-rSK1 is involved in cell signaling
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
-
binding site of SPHK1: involves Gly82, nucleotide binding also involved the SGDGX17-21K motif in the C2-region
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
K+
Mg2+
Mn2+
Ca2+
Ca2+-dependent calmodulin binding of recombinant wild-type and mutant enzymes
Ca2+
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
Mg2+
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
Mn2+
both isoforms (longrSK1 and rSK1) require divalent cations for their activity, both enzymes show the highest activity with Mg2+, followed by Mn2+ and Ca2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1S)-1-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol
i.e. ZINC19691372
-
(1S,3R)-1-(3,4-dihydroxyphenyl)-2,3,4,9-tetrahydro-1H-b-carboline-3-carboxylic acid
i.e. ZINC00095976
-
(2R)-1-[5-methoxy-2-([[2-(methylsulfanyl)ethyl]amino]methyl)phenoxy]-3-(4-methylpiperazin-1-yl)propan-2-ol
i.e. ZINC20254629
-
(2R)-2-amino-4-(4-octylphenyl)butan-1-ol
-
i.e. (R)-2-amino-4-(4-octylphenyl)butan-1-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S)-2-[[(4-octylphenyl)amino]methyl]pyrrolidin-3-ol
-
inhibition of isoform Sk1
(2R,3S)-3-amino-4-morpholin-4-yl-1-phenylbutan-2-ol
-
i.e. (2R,3S)-3-amino-4-morpholino-1-phenylbutan-2-ol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
potent, water-soluble, isoenzyme-specific inhibitor of SphK1. The inhibitor decreases growth and survival of human leukemia U937 and Jurkat cells, and enhances apoptosis and cleavage of Bcl-2. Lethality of SK1-I is reversed by caspase inhibitors and by expression of Bcl-2. The specific inhibitor of SphK1 warrants attention as potential addition to the therapeutic armamentarium in leukemia
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
-
-
(2S)-1-(1,3-benzodioxol-5-yloxy)-3-[benzyl(2-hydroxyethyl)amino]propan-2-ol
i.e. ZINC03253280
-
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
-
-
(2S)-1-(azepan-1-yl)-3-(1,3-benzodioxol-5-yloxy)propan-2-ol
i.e. ZINC02686881
-
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
-
-
(2S)-2-(3-[6-[(3-bromophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 35% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(3-chlorophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 46% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-bromophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 49% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-chlorophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 56% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-cyanophenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 43% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[(4-methylphenyl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 94% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[([1,1'-biphenyl]-4-yl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 51% residual activity at 0.001 mM
-
(2S)-2-(3-[6-[2-([1,1'-biphenyl]-4-yl)-2-oxoethoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 77% residual activity at 0.001 mM
-
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
potent and selective isoform SphK2 inhibitor
-
(2S)-2-[3-(6-butoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 69% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 65% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[2-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 47% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[3-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 34% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[2-[4-(trifluoromethyl)phenyl]ethoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 30% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[[3-(trifluoromethyl)phenyl]methoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform isoform SphK2 shows 81% residual activity at 0.001 mM
-
(2S)-2-[3-(6-[[4-(trifluoromethyl)phenyl]methoxy]naphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5091592, isoform SphK2 shows 42% residual activity at 0.001 mM
-
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
potent and selective isoform SphK2 inhibitor
-
(2S)-2-[3-[4-(octyloxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLM6031434, the inhibitor is 23fold selective for isoform SphK2 over SphK1 with 51% inhibition of isoform SphK2 at 0.0003 mM
-
(2S)-2-[3-[4-(octyloxy)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
8% inhibition of isoform SphK2 at 0.001 mM
-
(2S)-2-[3-[6-(2-methoxyethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 87% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 74% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(benzyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 97% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(cyclopentylmethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 57% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(heptyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 83% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5011416, isoform SphK2 shows 64% residual activity at 0.001 mM; SLC5091592, isoform SphK2 shows 42% residual activity at 0.001 mM
-
(2S)-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5081308, isoform SphK2 shows 51% residual activity at 0.001 mM
-
(2S)-2-[[(2R)-3-(9H-carbazol-9-yl)-2-hydroxypropyl]amino]butanedioic acid
i.e. ZINC02707482
-
(2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3R)-2-amino-N-(4-octylphenyl)-3-hydroxybutanamide
-
inhibition of isoform Sk1
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression; inhibits both isoforms SK1 and SK2. Treatment triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression
(2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol
-
i.e. (2S,3S)-2-amino-4-(4-octylphenyl)butane-1,3-diol, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
(2S,3S)-3-hydroxy-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5121314, isoform SphK2 shows 53% residual activity at 0.001 mM
-
(2S,3S)-3-hydroxy-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
SLC5111312, isoform SphK2 shows 46% residual activity at 0.001 mM
-
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
-
inhibition of isoform Sk1
(3aR,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid
i.e. ZINC05033974
-
(3R,4R,5S)-2-(6-amino-9H-purin-9-yl)-5-methyltetrahydrofuran-3,4-diol
i.e. ZINC17005625
-
(3S)-1-([4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl]methyl)pyrrolidin-3-ol
-
-
(3S)-N-[(1S)-1-[4-[5-(2-cyclohexylethyl)-1,2,4-oxadiazol-3-yl]phenyl]propyl]-3-hydroxy-L-prolinamide
-
-
(4-dodecylphenyl)[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(4-dodecylphenyl)[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
-
(4R)-4-(4-hydroxy-3-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol
i.e. ZINC01719191
-
(E)-3-(3-(4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)-6-methoxyquinolin-2(1H)-one
-
-
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(E)-6-methoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
-
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
-
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
-
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
-
(S)-2-((3-(4-((4-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5yl)methyl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(2-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
35% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(2-chloro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
40% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3,5-dimethyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
23% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-(pyridin-4-yl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
8% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
66% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
SLM6071469, the inhibitor is 73fold selective for isoform SphK2 over SphK1 with 65% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-allyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
59% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-bromo-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
24% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-chloro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
33% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
52% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-ethyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
42% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-fluoro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
23% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
67% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-methoxy-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
15% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
3% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-nitro-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
33% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
60% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(4'-fluoro-6-((4-(trifluoromethyl)benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
31% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
-
(S)-2-(3-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
2% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
-
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
-
(S)-2-(3-(4?-(trifluoromethyl)-6-((4-(trifluoromethyl)-benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
12% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(3-(6-((4-(trifluoromethyl)benzyl)oxy)-[1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
28% inhibition of isoform SphK2 at 0.0003 mM
-
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
-
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
-
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
-
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
-
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium chloride
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
-
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
-
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
-
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
-
1-(3-(4-((4-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
-
-
1-(4-octylphenethyl)piperidin-4-ol
a selective inhibitor of isozyme SK1, structure-activity relationship profile
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
-
1-methyl-1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium
-
1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol
-
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
-
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
-
1-[[4-(4-tert-butylphenoxy)-3-fluorophenyl]methyl]pyrrolidin-3-ol
-
-
2-(4-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-N-(prop-2-en-1-yl)hydrazinecarbothioamide
i.e. ZINC12651592
-
2-(4-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-N-phenylhydrazinecarbothioamide
i.e. ZINC19419587
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
2-[(1R)-1-amino-2-methylpropyl]-6-hydroxypyrimidin-4(3H)-one
i.e. ZINC82450359
-
2-[(2S)-2-aminobutan-2-yl]-6-hydroxypyrimidin-4(3H)-one
i.e. ZINC82450459
-
2-[(2S)-4-[(2-aminopyrimidin-5-yl)methyl]-1-[(2-methylphenyl)methyl]piperazin-2-yl]ethan-1-ol
i.e. ZINC19759036
-
3-(((4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)amino)methyl)-6,7-dimethoxyquinolin-2(1H)-one
-
-
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
-
-
3-O-sulfogalactosylceramide
-
endogenous glycolipid sulfatide, binds to and inhibits the activity of isoform Sphk2 and the closely related ceramide kinase Cerk, but not isoform Sphk1. The lipid binding domain is mapped to the N-terminus of Sphk2, residues 1-175, a region of sequence that is absent in Sphk1, but aligns with a pleckstrin homology domain in Cerk
4-[5-[(1S)-6-hydroperoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-6-hydroxy-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]benzoic acid
i.e. ZINC16995081
-
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
selective inhibition of isoform SK2
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
inhibits both isoforms SK1 and SK2; inhibits both isoforms SK1 and SK2
5-([(3S)-3-(2-hydroxyethyl)-4-[(6-methylpyridin-2-yl)methyl]piperazin-1-yl]methyl)-2-methoxyphenol
i.e. ZINC19792941
-
5-[[2-(3-methylphenyl)hydrazinyl]methylidene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
i.e. ZINC00221579
-
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6-hydroxy-5-[2-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]pentyl]-2-methylpyrimidin-4(3H)-one
i.e. ZINC18996465
-
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
-
6-[5-[(2S)-1-carbamimidoylpyrrolidin-2-yl]-1,2,4-oxadiazol-3-yl]naphthalen-2-yl 4-methylbenzene-1-sulfonate
isoform SphK2 shows 89% residual activity at 0.001 mM
-
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
-
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
-
Cutsum
-
detergent, required for sphinganine suspension, 0.05 mg/ml gives optimal rates, inhibition above 1 mg/ml
-
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulphate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
L-erythro-sphingosine
0.005 mM, 41% inhibition; 0.005 mM, 43% inhibition
Melatonin
-
melatonin decreases enzymic activity in PC-3 cells during hypoxia. In addition, Melatonin inhibits the stability of hypoxia inducible factor 1alpha in a time- and concentration-dependent manner and suppresses AKT/glycogen synthase kinase-3beta signaling pathway
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
potent and selective isoform SphK2 inhibitor
-
N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
selective inhibition of isoform SK1
N-cyclohexyl-N-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)acetamide
-
N-[(1R)-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1R)-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((R)-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S)-1-methyl-3-phenylpropyl]hexadecanamide
-
i.e. N-((R)-1-hydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]tridecanamide
-
i.e. N-((2S,3R)-1,3-dihydroxy-4-phenylbutan-2-yl)tridecanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2R)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3R)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-3-phenylpropyl]hexadecanamide
-
i.e. N-((2S,3S)-1,3-dihydroxy-4-phenylbutan-2-yl)palmitamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-1-(morpholin-4-ylmethyl)-3-phenylpropyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-1-morpholino-4-phenylbutan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]decanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)decanamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
N-[(1S,2S)-2-hydroxy-3-phenyl-1-(pyrrolidin-1-ylmethyl)propyl]octadecanamide
-
i.e. N-((2S,3S)-3-hydroxy-4-phenyl-1-(pyrrolidin-1-yl)butan-2-yl)stearamide, synthetic sphingosine analogue, specific inhibition of isozymes SphK1 and SphK2
phosphatidylinositol 4,5-bisphosphate
-
0.01 mM, isoform SphK2, 60% of initial activity, isoform SphK1, 90% of initial activity
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
phytosphingosine
0.0025 mM, 21% inhibition; 0.0025 mM, 64% inhibition
SG-12
i.e. (2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol, potent and selective isoform SphK2 inhibitor
-
SLM6031434
the inhibitor is 23fold selective for isoform SphK2 over SphK1 with 51% inhibition of isoform SphK2 at 0.0003 mM
-
SLM6071469
i.e. (S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide. The inhibitor is 73fold selective for isoform SphK2 over SphK1 with 65% inhibition of isoform SphK2 at 0.0003 mM
-
sphingosine kinase inhibitor
-
can influence co-stimulatory molecules (CD40, CD80, CD86 and MHC class II) and cytokine production (IL-12 and IL-10) in murine bone marrow-derived dendritic cells. Sphingosine kinase inhibitor significantly inhibits co-stimulatory molecules in dendritic cells. Sphingosine kinase inhibitor suppresses IL-12 production by dendritic cells and IFN-gamma production by T cells
-
(2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
i.e. SK1-I, BML-258, isotype-specific SphK1 inhibitor. Treatment suppresses growth of LN229 and U373 glioblastoma cell lines and nonestablished human GBM6 cells. SK1-I also enhances glioblastoma multiforma cell death and inhibits their migration and invasion. Sk1-I enhances the survival of mice harboring LN229 intracranial tumors. SK1-I rapidly reduces phosphorylation of Akt but has no significant effect on activation of extracellular signal-regulated kinase 1/2
(2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol
-
i.e. SK1-I, BML-258, isotype-specific SphK1 inhibitor. SK1-I markedly reduces the tumor growth rate of glioblastoma xenografts, inducing apoptosis and reducing tumor vascularization, and enhances the survival of mice harboring LN229 intracranial tumors
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
specific inhibitor for isoform SphK2
-
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
potent and selective isoform SphK2 inhibitor
-
(S)-FTY720 vinylphosphonate
uncompetitive with sphingosine and is a mixed inhibitor with respect to ATP
(S)-FTY720 vinylphosphonate
uncompetitive, binds to a putative allosteric site in the enzyme contingent on formation of the enzyme-sphingosine complex. (S)-FTY720 vinylphosphonate binding to and stabilization of the allosteric site might enhance the autoinhibitory effect on the enzymic activity
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
i.e. SKi, or SKI-II. Mixed inhibitor of sphingosine and ATP binding. N-terminal 86 amino-acid isoform variant SK1b shows reduced sensitivity to proteasomal degradation induced by 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole in comparison to isoform SK1a
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold; inhibits both isoforms SK1 and SK2. Treatment increases mRNAs for both isoforms SK1 and SK2 by about 4fold
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
-
2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
a dual SphK1/2 inhibitor; a dual SphK1/2 inhibitor
2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole
-
the inhibition of SPHK affects acute eosinophilic inflammation induced in antigen-challenged mouse model
2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole
0.001-0.008 mM, specific inhibition
B-5354c
-
SphK1 inhibitor, induces apoptosis in a caspase-dependent manner by tilting the ceramide/sphingosine 1-phosphate rheostat toward ceramide. Pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
DL-threo-dihydrosphingosine
-
treatment of Jurkat and U-937 cells induces apoptosis and produces dramatic increases in SphK1 expression, the latter being a result of apoptotic stress
docetaxel
-
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
FTY720
i.e. fingolimod, competitive with sphingosine and uncompetitive with ATP
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
-
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione, potent and selective isoform SphK2 inhibitor
-
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione, isoform SphK2-selective inhibitor
-
K145
i.e. (5E)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione, isoform SphK2-selective inhibitor
-
N,N-dimethylsphingosine
-
inhibition of both isoforms Sphk1 and Sphk2. Treatment of Jurkat and U-937 cells results ina large increase in expression of SphK1 concomitant with induction of apoptosis
N,N-dimethylsphingosine
-
decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
N,N-dimethylsphingosine
-
the inhibition of SPHK affects acute eosinophilic inflammation induced in antigen-challenged mouse model
N,N-dimethylsphingosine
-
suppression of SphK1 by its inhibitor, N,N-dimethylsphingosine, or siRNA results in decreased mRNA expression of TNF-alpha, IL-1beta and iNOS and release of TNF-alpha and nitric oxide in lipopolysaccharid-activated microglia
N,N-dimethylsphingosine
competitive inhibition with D-erythro-sphingosine as substrate
PF-543
potent, selective, sphingosine-competitive isoform SphK1 inhibitor
SKI-II
-
isoform Sk1-specific inhibitor. Treatment markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
SKI-II
highly selective and non ATP-competitive, enzyme binding structure, overview
SKI-II
i.e. 4-[[4-(4-chlorophenyl)thiazol-2-yl]amino]phenol, isoform SphK1-selective inhibitor
SKI-II
i.e. 4-[[4-(4-chlorophenyl)thiazol-2-yl]amino]phenol; i.e. 4-[[4-(4-chlorophenyl)thiazol-2-yl]amino]phenol
Triton X-100
-
the enzyme activity is higher with substrate solubilized by bovine serum albumin compared to Triton X-100
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
-
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
-
additional information
-
inhibitors of isozyme SphK2 are cytotoxic, overview, inhibitory potency of the synthetic sphingosine analogues on isozymes SphK1 and SphK2, overview
-
additional information
-
isoform Sphk2 binds to phosphatidylinositol monophosphates but not to abundant cellular phospholipids
-
additional information
-
short-term androgen removal induces a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that is not observed in the hormone-insensitive PC-3 cells. The addition of dihydrotestosterone to androgen-deprived LNCaP cells re-establishes cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 can markedly impede the effects of dihydrotestosterone
-
additional information
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-(4-methylphenethyl)piperidin-4-amine, 1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium, and 1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium, while potential inhibitors (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone, 4-octyl-N-(pyridin-4-ylmethyl)benzamide, N-(4-hydroxyphenyl)-4-octylbenzamide, 4-(4-octyl-1H-1,2,3-triazol-1-yl)phenol, and 2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethanol are slightly activating; design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-(4-methylphenethyl)piperidin-4-amine, 1-(4-octylphenethyl)piperidin-4-amine, 1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, and 1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, while potential inhibitors 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, [(2S)-1-[2-(4-octylphenyl)ethyl]pyrrolidin-2-yl]methanol, and (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone are slightly activating
-
additional information
design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-(4-methylphenethyl)piperidin-4-amine, 1-[2-[4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]-1-methylpiperidinium, and 1-methyl-1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidinium, while potential inhibitors (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone, 4-octyl-N-(pyridin-4-ylmethyl)benzamide, N-(4-hydroxyphenyl)-4-octylbenzamide, 4-(4-octyl-1H-1,2,3-triazol-1-yl)phenol, and 2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethanol are slightly activating; design, synthesis, and evaluation of the potency of isoform-selective inhibitors of sphingosine kinases 1 and 2 using SK1 inhibitor RB-005 as lead compound, structure-activity relationships and molecular modeling of sphingosine kinase inhibitors, overview. No or poor inhibition by 1-(4-methylphenethyl)piperidin-4-amine, 1-(4-octylphenethyl)piperidin-4-amine, 1-[2-[4-(4-pentyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, and 1-[2-[4-(4-octyl-1H-1,2,3-triazol-1-yl)phenyl]ethyl]piperidin-4-ol, while potential inhibitors 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, 1-[2-(4-hexylphenyl)ethyl]piperidin-4-ol, [(2S)-1-[2-(4-octylphenyl)ethyl]pyrrolidin-2-yl]methanol, and (4-hydroxypiperidin-1-yl)(4-octylphenyl)methanone are slightly activating
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview; structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
additional information
structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview; structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors, SphK1- and SphK2-selective inhibitors, discovery of selective, nanomolar inhibitors, chemical synthesis, overview
-
additional information
-
not inhibitory: DL-threo-dihydrosphingosine
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-(3-[6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2 shows 104% activity at 0.001 mM
-
(2S)-2-[3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 106% activity at 0.001 mM
-
(2S)-2-[3-[6-(2-methoxyethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 118% activity at 0.001 mM
-
(2S)-2-[3-[6-(2-oxo-2-phenylethoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 103% activity at 0.001 mM
-
(2S)-2-[3-[6-(3-methoxypropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2 shows 109% activity at 0.001 mM
-
11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid
-
treatment markedly augments SK activity in HUVECs. At the concentration of 1 mM, 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid increases SK activity by 110% and the maximal effect on SK activation is observed at 20 min after 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid addition. Inhibition of SK by a specific inhibitor, SKI-II, markedly attenuates 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation. 11,12-Epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced activation of Akt kinase and transactivation of the epidermal growth factor receptor are also inhibited by SKI-II
12-O-tetradecanoylphorbol-13-acetate
50 nM, maximum increase in activity after 24 h
bovine serum albumin
-
the enzyme activity is higher with substrate solubilized by bovine serum albumin compared to Triton X-100
-
Calmodulin
Ca2+-dependent binding of recombinant wild-type and mutant enzymes
camptothecin
0.003 mM camptothecin induces marked elevation of SPHK activity, reaching a maximal level with approximately 250% of the control untreated cells at 36 h
Cutsum
-
detergent, required for sphinganine suspension, 0.05 mg/ml gives optimal rates, inhibition above 1 mg/ml
-
endothelin-1
1 nM, 2.4fold and 2.7fold increase of activity after 5 and 10 min, respectively
galactosylceramide
-
0.01 mM, isoform SphK2, 84% of initial activity, isoform SphK1, 109% of initial activity
galactosylceramide 3-sulfate
-
0.01 mM, isoform SphK2, 37% of initial activity, isoform SphK1, 156% of initial activity
heregulin
-
heregulin stimulates SphK1 activity only in filamin A-expressing A7 melanoma cells but not in filamin A-deficient cells and induces its translocation and colocalization with filamin A at lamellipodia. SphK1 is required for heregulin-induced migration, lamellipodia formation, activation of PAK1, and subsequent filamin A phosphorylation. Sphingosine 1-phosphate directly stimulates PAK1 kinase. Heregulin also induces colocalization of S1P1, the promotility sphingosine 1-phosphate receptor, but not S1P2, with SphK1 and filamin A at membrane ruffles
-
lipopolysaccharide
-
increases Sk1 transcription which is accompanied by increased SK activity and generation of sphingosine 1-phosphate. Sphingosine 1-phosphate is able to cause increases in COX-2 and PGE2 levels in RAW cells
N,N-dimethylsphingosine
0.005 mM, activation to 106% of control
phosphatidylinositol 4-phosphate
-
0.01 mM, isoform SphK2, 89% of initial activity, isoform SphK1, 175% of initial activity
thrombin
-
stimulation of the lung epithelial cell line A-549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine 1-phosphate, abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin. PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells is also dependent on SPHK1
-
N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide
-
i.e. K6PC-5, induces intracellular Ca2+ concentration oscillations in HaCaT cells. The K6PC-5-induced intracellular Ca2+ oscillations are dependent on thapsigargin-sensitive Ca2+ stores and Ca2+ entry, but independent of the classical phospholipase C-mediated pathway. K6PC-5 enhances the expression of involucrin and filaggrin, specific differentiation-associated marker proteins in HaCaT cells, whereas transfection of SphK1 siRNA blocks the increase of involucrin
N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide
-
i.e. K6PC-5, activates SphK in a dose-dependent manner. K6PC-5 induces mobilization in hairless mouse epidermis. Both dimethylsphingosine and dihydroxysphingosine, SphK inhibitors, and transfection of SphK1-siRNA blocks K6PC-5-induced increases in intracellular Ca2+ concentration
phosphatidic acid
-
0.01 mM, isoform SphK2, 102% of initial activity, isoform SphK1, 265% of initial activity
additional information
-
the enzyme is stimulated by the phytohormone abscisic acid in guard cells and mesophyll cell protoplasts
-
additional information
-
selective activation mechanism of isozymes, overview, isozyme SPHK2 is activated by high ionic strength
-
additional information
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
-
solubilization in Triton X-100 results in higher activity compared to bovine serum albumin
-
additional information
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
-
not activated by histamine or 12-O-tetradecanoylphorbol-13-acetate
-
additional information
not stimulated by phosphatidylcholine or phosphatidylethanolamine
-
additional information
not stimulated by phosphatidylcholine or phosphatidylethanolamine
-
additional information
SPHK2 is not activated by transforming growth factor beta1
-
additional information
SPHK2 is not activated by transforming growth factor beta1
-
additional information
-
SPHK2 is not activated by transforming growth factor beta1
-
additional information
-
under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.02
ATP
recombinant wild-type enzyme, pH and temperature not specified in the publication
0.0255
ATP
recombinant mutant D81N enzyme, pH and temperature not specified in the publication
0.0628
ATP
pH and temperature not specified in the publication, mutant E180Q
0.071
ATP
pH and temperature not specified in the publication, mutant G113A
0.073
ATP
pH and temperature not specified in the publication, mutant K27A
0.0774
ATP
pH and temperature not specified in the publication, mutant D176N
0.078
ATP
pH and temperature not specified in the publication, mutant K29A
0.0884
ATP
pH and temperature not specified in the publication, mutant D178N
0.09
ATP
pH and temperature not specified in the publication, mutant G26A
0.092
ATP
pH and temperature not specified in the publication, mutant K103R
0.0947
ATP
pH and temperature not specified in the publication, mutant E182Q
0.124
ATP
pH and temperature not specified in the publication, mutant S79A
3.8
ATP
pH and temperature not specified in the publication, mutant G82A
0.00247
D-erythro-sphingosine
pH and temperature not specified in the publication, deletion mutant DELTA364-384
0.0102
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant E182Q
0.014
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K103R
0.018
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G26A
0.019
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K29A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G113A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant K27A
0.02
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant S79A
0.022
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant G82A
0.0257
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant E180Q
0.0366
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant D176N
0.108
D-erythro-sphingosine
pH and temperature not specified in the publication, mutant D178N
1
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 10 microM 3-O-sulfogalactosylceramide
1.7
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 25 microM 3-O-sulfogalactosylceramide
3.6
nitrobenzoxadiazole-labeled sphingosine
-
pH 7.4, 35°C, presence of 4 microM 3-O-sulfogalactosylceramide
0.0076
sphingosine
in 50 mM HEPES, pH 7.4, 10 mM KCl, 15 mM MgCl2, 0.1% Triton X-100, 20% glycerol, 2 mM orthovanadate, 2 mM dithiothreitol, 10 mM NaF, and 1 mM deoxypyridoxine
0.01
sphingosine
pH 7.4, 37°C, recombinant wild-type enzyme and mutant E181Q
additional information
additional information
-
simple quantitative radio-assay
-
additional information
additional information
-
assay for measurement of intracellular levels of free sphingoid bases
-
additional information
additional information
Michaelis-Menten kinetics
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
-
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
-
kinetics, isozymes SPHK1 and SPHK2
-
additional information
additional information
kinetics, recombinant wild-type and mutant enzymes
-
additional information
additional information
-
kinetics, recombinant wild-type and mutant enzymes
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
substrate kinetic analysis
-
additional information
additional information
enzyme is an oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
-
additional information
additional information
kinetic values of wild-type and mutant enzymes, overview
-
additional information
additional information
kinetic values of wild-type and mutant enzymes, overview
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0065
ATP
recombinant mutant D81N enzyme, pH and temperature not specified in the publication
0.0427
ATP
recombinant wild-type enzyme, pH and temperature not specified in the publication
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000047 - 0.0042
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
-
0.000075 - 0.003
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
-
0.00009 - 0.00012
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
-
0.000089 - 0.0065
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
0.00037
(2S)-2-[3-[4-(octyloxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.00102 - 0.0038
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
-
0.00098
(2S)-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00098
(2S,3S)-3-hydroxy-2-[3-[6-(2-methylpropoxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0009
(2S,3S)-3-hydroxy-2-[3-[6-(pentyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
-
0.083 - 0.1
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
0.088 - 0.096
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
0.000197
(S)-2-(3-(3-(tert-butyl)-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000089
(S)-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000186
(S)-2-(3-(3-cyclopropyl-4-((4-(trifluoromethyl)-benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000192
(S)-2-(3-(3-isopropyl-4-((4-(trifluoromethyl)benzyl)-oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.000201
(S)-2-(3-(3-propyl-4-((4-(trifluoromethyl)benzyl)oxy)-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.042 - 0.096
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
0.085 - 0.094
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
0.012 - 0.075
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
0.091 - 0.1
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
0.09 - 0.095
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
0.095 - 0.1
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
0.077 - 0.08
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
0.1
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.09 - 0.094
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
0.056 - 0.098
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
0.091 - 0.095
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
0.075
1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)guanidine
pH and temperature not specified in the publication
0.0001 - 0.0103
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.00004 - 0.0141
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.00098 - 0.0117
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.00007 - 0.0099
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.00044 - 0.006
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.00032 - 0.008
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.0025 - 0.011
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.043 - 0.055
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
-
0.0004 - 0.0102
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
0.0002 - 0.0081
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
0.003 - 0.0034
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
-
0.0012 - 0.0016
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
-
0.0093
5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.0031 - 0.0042
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
0.00002
Amgen 82
isoform SphK2, pH and temperature not specified in the publication
-
0.069 - 0.092
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
0.07 - 0.096
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
0.065 - 0.098
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
0.00028
N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-cyclohexylacetamide
pH not specified in the publication, temperature not specified in the publication
0.055
N-[(2S)-1-amino-1-iminopropan-2-yl]-3-octylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.016
SLP-120701
IC50 above 100 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.0014
SLR080811
isoform SphK2, pH and temperature not specified in the publication
0.000125
(2S)-1-(3-dodecylbenzoyl)pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0015
(2S)-1-(3-dodecylbenzoyl)pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.000047
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0042
(2S)-1-(4-[4-[3-(2-cyclohexylethyl)phenyl]-1,3-oxazol-2-yl]benzoyl)pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.000075
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.003
(2S)-1-[3-[7-(cyclohexylmethoxy)heptyl]benzoyl]pyrrolidine-2-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00009
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.00012
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
isoform SphK1, at pH 8.0 and 25°C
-
0.000089
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, at pH 8.0 and 25°C
-
0.0065
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK1, at pH 8.0 and 25°C
-
0.00102
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0038
(2S)-2-[3-[6-(hexyloxy)naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.014
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
pH not specified in the publication, temperature not specified in the publication
0.016
(2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol
pH not specified in the publication, temperature not specified in the publication
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
isoform SphK2, at pH 8.0 and 25°C
-
0.0064
(5Z)-3-(2-aminoethyl)-5-[3-(4-butoxyphenyl)propylidene]-1,3-thiazolidine-2,4-dione
isoform SphK2, pH and temperature not specified in the publication
-
0.044
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.093
(R)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.083
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.1
(R)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.088
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.096
(R)-amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.078
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
pH and temperature not specified in the publication
0.09
(S)-1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-guanidine
pH and temperature not specified in the publication
0.07
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
pH and temperature not specified in the publication
0.094
(S)-1-(2-methyl-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-propyl)guanidine
pH and temperature not specified in the publication
0.092
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
pH and temperature not specified in the publication
0.096
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboximidamide
pH and temperature not specified in the publication
0.088
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.098
(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
pH and temperature not specified in the publication
0.042
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.096
(S)-2-(5-(4-octylphenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.085
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
pH and temperature not specified in the publication
0.094
(S)-amino((2-hydroxy-1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)methaniminium
pH and temperature not specified in the publication
0.012
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.075
(S)-amino(2-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-methyl)pyrrolidin-1-yl)methaniminium chloride
pH and temperature not specified in the publication
0.091
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.1
(S)-amino(2-((4-decylphenyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.09
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.095
(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.095
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.1
(S)-amino(2-((4-octylbenzyl)carbamoyl)pyrrolidin-1-yl)-methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.077
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.08
(S)-amino(2-(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-ethyl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.09
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.094
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-2,5-di-hydro-1H-pyrrol-1-yl)methaniminium 2,2,2-trifluoroacetate
pH and temperature not specified in the publication
0.056
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.098
(S)-amino(2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)-piperidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.091
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.095
(S)-amino(2-(5-(4-octylphenyl)-1,2,4-oxadiazol-3-yl)-pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.088
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
pH and temperature not specified in the publication
0.099
1-(1-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)-guanidine
pH and temperature not specified in the publication
0.0003
1-carbamimidoyl-N-(3-dodecylphenyl)cyclopropane-1-carboxamide
isoform SphK1, pH and temperature not specified in the publication
-
0.006
1-carbamimidoyl-N-(3-dodecylphenyl)cyclopropane-1-carboxamide
isoform SphK2, pH and temperature not specified in the publication
-
0.09
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
pH and temperature not specified in the publication
0.098
1-methyl-1-((3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-guanidine
pH and temperature not specified in the publication
0.0001
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0103
1-[3-(3-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00004
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0141
1-[3-(3-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00098
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0117
1-[3-(3-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00007
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0099
1-[3-(3-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00044
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.006
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.00032
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.008
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0025
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.011
1-[3-(4-tridecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.043
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.055
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0004
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0102
1-[5-(3-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0002
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0081
1-[5-(3-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.003
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0034
1-[5-(4-dodecylphenyl)-1,2,4-oxadiazol-3-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0012
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0016
1-[5-(4-dodecylphenyl)-1,3,4-oxadiazol-2-yl]cyclopropane-1-carboximidamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0079
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH not specified in the publication, temperature not specified in the publication
0.016
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH not specified in the publication, temperature not specified in the publication
0.017
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH 7.4, 30°C, competitive inhibition
0.048
2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole
pH 7.4, 30°C, uncompetitive inhibition
0.0031
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.0042
5-(4-chlorophenyl)-N-[2-(3,4-dihydroxyphenyl)ethyl]tricyclo[3.3.1.13,7]decane-2-carboxamide
pH not specified in the publication, temperature not specified in the publication
0.069
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.092
amino((1S,3S)-3-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.07
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.096
amino((1S,4S)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.065
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.098
amino((2S,4R)-4-hydroxy-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.084
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.09
amino(3-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl)azetidin-1-yl)methaniminium
pH and temperature not specified in the publication
0.008
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
isoform SphK2, at pH 8.0 and 25°C
-
0.06
N,N-dimethyl-4-(3-octylphenyl)-N-propylcyclohexan-1-aminium
isoform SphK1, at pH 8.0 and 25°C
-
0.0002
N-(1-carbamimidoylcyclopropyl)-3-dodecylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0005
N-(1-carbamimidoylcyclopropyl)-3-dodecylbenzamide
isoform SphK2, pH and temperature not specified in the publication
-
0.0046
N-(1-carbamimidoylcyclopropyl)-4-dodecylbenzamide
isoform SphK1, pH and temperature not specified in the publication
-
0.0109
N-(1-carbamimidoylcyclopropyl)-4-dodecylbenzamide
isoform SphK2, pH and temperature not specified in the publication
-
0.02
VPC94075
isoform SphK2, pH and temperature not specified in the publication
-
0.055
VPC94075
isoform SphK1, pH and temperature not specified in the publication
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00002
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-([4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]ethyl]piperidin-4-ol
Homo sapiens
isoform SphK2, pH and temperature not specified in the publication
-
0.00028
(2S)-2-([3-[4-([4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino)phenyl]-1,2,4-oxadiazol-5-yl]methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.00043
(2S,3S)-3-hydroxy-N-(4-octylbenzyl)pyrrolidine-2-carboxamide
Homo sapiens
-
pH 7.5, 22°C
0.000062
(2S,3S)-3-hydroxy-N-(4-octylphenyl)pyrrolidine-2-carboxamide
Homo sapiens
-
pH 7.5, 22°C
0.0282
(E)-3-(3-(4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)-6-methoxyquinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0071 - 0.0141
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
-
0.0031
(E)-6-methoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.000234
(S)-2-((3-(4-((4-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000359
(S)-2-((3-(4-((4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000391
(S)-2-((3-(4-((4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000266
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.00064
(S)-2-((3-(4-((4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000452
(S)-2-((3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000687
(S)-2-((3-(4-((4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000254
(S)-2-((3-(4-((4-butyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000248
(S)-2-((3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000396
(S)-2-((3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5yl)methyl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000909
(S)-2-(3-(4-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000269
1-(3-(4-((4-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000717
1-(3-(4-((4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.000261
1-(3-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)cyclopropanecarboximidamide
Homo sapiens
isoform SphK2, at pH 8.0 and 25°C
-
0.0591
3-(((4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenyl)amino)methyl)-6,7-dimethoxyquinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0439
4-((4-(4-chlorophenyl)pyrimidin-2-yl)amino)phenol
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0156 - 0.0157
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
0.0139 - 0.0187
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
0.0079 - 0.0089
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
-
0.0024
dimethylsphingosine
Rattus norvegicus
at 37°C, in the presence of 0.25% Triton X-100
0.0024
DL-threo-dihydrosphingosine
Rattus norvegicus
at 37°C, in the presence of 0.25% Triton X-100
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
-
0.0071
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0141
(E)-6,7-dimethoxy-3-(3-(4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)-3-oxoprop-1-en-1-yl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0107
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0182
3-((4-(4-chlorophenyl)pyrimidin-2-yl)-1-yl)oxymethyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0156
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0157
6,7-dihydroxy-3-(((4-((4-(naphthalene-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0139
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.0187
6,7-dimethoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0079
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK1, at pH 7.4 and 37°C
-
0.0089
6-methoxy-3-(((4-((4-(naphthalen-2-yl)pyrimidin-2-yl)amino)phenyl)amino)methyl)quinolin-2(1H)-one
Homo sapiens
isoform SphK2, at pH 7.4 and 37°C
-
0.002
CB5468139
Homo sapiens
IC50 above 0.01 mM, isoform SphK1, at pH 8.0 and 25°C
-
100
CB5468139
Homo sapiens
IC50 above 100 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.01
SLP7111228
Homo sapiens
IC50 above 0.01 mM, isoform SphK2, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
Homo sapiens
IC50 below 0.0000017 mM, isoform SphK1, at pH 8.0 and 25°C
-
0.0000017
[(2R)-1-([4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl)pyrrolidin-2-yl]methanol
Homo sapiens
IC50 below 0.0000017 mM, isoform SphK2, at pH 8.0 and 25°C
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
additional information
Vmax of different splicing variants of both isozymes
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.5
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 8.5
-
pH 6: about 55% of maximum activity, pH 8.5: about 40% of maximum activity
6 - 9
-
pH 6: about 35% of maximum activity, pH 9: about 70% of maximum activity
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
isozymes SgkA and SgkB encoded by the genes sgkA and sgkB
-
-
brenda
isozyme Sk1; 2 isozymes Sk1 and Sk2 encoded by 2 genes Sk1 and Sk2
SwissProt
brenda
isozyme Sk2; 2 isozymes Sk1 and Sk2 encoded by 2 genes Sk1 and Sk2
SwissProt
brenda
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685792, 686643, 689845, 689847, 701617, 701975, 702037, 702597, 702659, 702853, 702951, 703015, 703025, 703085, 703121, 703122, 703218, 703252, 703254, 703463, 703464, 703611, 703616, 704041, 704044, 704071, 704072, 704087, 704448, 704592, 704989, 705438, 705656, 705658, 705684, 705686, 706074, 706448, 706681, 721418
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-
brenda
2 isozymes SPHK1 and SPHK2, several splicing variants exist, overview
-
-
brenda
enzyme is expressed as isoform SK1a of 42.5 kDa, and isoform SK1b, a 51 kDa protein identical to SK1a, but with an 86 amino acid N-terminal extension
SwissProt
brenda
isozyme SPHK1; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
brenda
isozyme SPHK2; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
brenda
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684360, 687057, 687107, 689070, 701632, 702089, 702503, 702659, 702853, 703025, 703086, 703087, 703090, 703236, 703613, 703616, 703951, 704041, 704152, 704795, 704945, 704946, 704989, 705438, 705938, 706008, 706578, 706681, 723077
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-
brenda
isozyme SPHK1; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
brenda
isozyme SPHK2; 2 isozymes SPHK1 and SPHK2, several splicing variants
SwissProt
brenda
male C57BL mice, 2 isozymes SPHK1 and SPHK2, isozyme SPHK1 exists in 2 splicing variants a and b
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-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
gracilis muscle resistance artery. Pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
brenda
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melanoma B16 cells, variant F10, Swiss 3T3, balb/c 3T3 clone A31
brenda
the majority of NK cells analyzed have very low sphingosine 1-phosphate phosphatase activity in comparison to sphingosine kinase activity, the majority of cells do not convert sphingosine 1-phosphate to any other detectable compound
brenda
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gracilis muscle resistance artery. Pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
brenda
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SPHK1, exclusively in the acrosome, spermatozoa contain 5 sphingosine 1-phosphate receptors
brenda
additional information
higher activity of isozyme SPHK1, low activity of isozyme SPHK2
brenda
higher activity of isozyme SPHK1, low activity of isozyme SPHK2
brenda
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white matter, cerebellum, cerebrum, red nucleus, cerebral peduncle
brenda
quite low activity of isozyme SPHK1 and isozyme SPHK2
brenda
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white matter, cerebellum, cerebrum, red nucleus, cerebral peduncle
brenda
expression pattern of Sk1 during embryogenesis
brenda
expression pattern of Sk2 during embryogenesis
brenda
-
in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed
brenda
-
in airway epithelium of a mouse asthmatic model, both SphK and MUC5AC expression are increased and proteins co-localize
brenda
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SPHK2 is expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of rheumatiod patients. In the cultured synovial fibroblasts from these patients, SPHK2 is more highly expressed than that in the human macrophage cell line, THP-1 and human dermal fibroblasts. SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of the cultured synovial fibroblasts
brenda
expression of long-rSK1 mRNA, no expression of rSK1 mRNA
brenda
high activity of isozyme SPHK2, low activity of isozyme SPHK1
brenda
expression of long-rSK1 mRNA, no expression of rSK1 mRNA
brenda
high activity of isozyme SPHK1, low activity of isozyme SPHK2
brenda
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from bone marrow. N,N-dimethyl-D-erythro-sphingosine inhibits osteoclastogenesis a sphingosine kinase independently of sphingosine kinase
brenda
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during gestation, isoforms Sphk1 and Sphk2 are co-expressed. The levels and activity of SphK1/2 are modest at midgestation , increase at day 19 and progressively decline to low at postpartum. Inhibition of protein kinase C and ERK reduces SphK1/2 activity. In primary cultures of myometrial cells from day 19 pregnant rats, induction of COX2 is mediated by 4-phorbol 12,13-dibutyrate and IL-1 through sequential activation of protein kinase C, ERK1/2, and SphK1. Sphingosine 1-phosphate produced by SphK1 is released in the medium. In day 12 myometrial tissues, the release of sphingosine 1-phosphate is markedly reduced in association with low levels of SphK1 and COX2
brenda
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sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells
brenda
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in the cultured synovial fibroblasts from rheumatoid arthritis patients, SPHK2 is more highly expressed than in the human macrophage cell line, THP-1 and human dermal fibroblasts
brenda
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epidermal growth factor regulates plasminogen activator inhibitor-1 by a pathway involving c-Src, PKCdelta, and sphingosine kinase 1 in glioblastoma cells
brenda
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N,N-dimethyl-D-erythro-sphingosine induces apoptotic cell death via modulation of mitochondrial membrane potential, c-Jun N-terminal protein kinase, p38 MAP kinase, extracellular signal-regulated kinase, and Akt kinase, but not through inhibition of sphingosine kinase or protein -kinase C in U937 cells
brenda
additional information
the 2 genes Sk1 and Sk2 show overlapping but distinct temporal and spatial expression patterns
brenda
additional information
the 2 genes Sk1 and Sk2 show overlapping but distinct temporal and spatial expression patterns
brenda
additional information
tissue distribution of isozyme SPHK1 and isozyme SPHK2 expression and activity, overview
brenda
additional information
tissue distribution of isozyme SPHK1 and isozyme SPHK2 expression and activity, overview
brenda
additional information
-
tissue distribution of isozyme SPHK1 and isozyme SPHK2 expression and activity, overview
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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enzymes cycles between trans-Golgi network and late endosomes, facing the cytosol
brenda
additional information
-
SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
brenda
isozyme SphK1 is mostly in the cytoplasm and migrates to the plasma membrane upon phosphorylation
brenda
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the cytosolic enzyme is 20fold less active than the membrane-associated enzyme
brenda
isozymes Sk1 and Sk2, predominantly
brenda
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enzymes cycles between trans-Golgi network and late endosomes, facing the cytosol
brenda
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75% of total activity in leaves, associated with, the cytosolic enzyme is 20fold less active than the membrane-associated enzyme
brenda
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deleting the N-terminal domain with residues 1-175 reduces Sphk2 membrane localisation in cells
brenda
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SPHK2 is expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine 1-phosphate
brenda
isozyme SK2 possess (and isozyme SK1 lacks) nuclear localization R88-R93 and export signal sequences L380-L389 that help to define subcellular localization and function
brenda
isozyme SphK1 is mostly in the cytoplasm and migrates to the plasma membrane upon phosphorylation
brenda
-
activation of Gq protein-coupled receptors induces a profound, rapid and long-lasting translocation of isoform SphK1 to the plasma membrane
brenda
additional information
-
subcellular localization depends on the tissue type
-
brenda
additional information
isozyme hSK1 lacks the nuclear localization R88-R93 and export signal sequences, in contrast to isozyme hSK2. Threonine 54 and asparagine 89 are required for the specific increase in affinity of hSK1 with vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol. Mutants T54A and N89A lose selective binding to POPC/POPS over POPC/POPG, whereas the S168A mutant maintain the selectivity shown by WT
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brenda
additional information
isozyme hSK1 lacks the nuclear localization R88-R93 and export signal sequences, in contrast to isozyme hSK2. Threonine 54 and asparagine 89 are required for the specific increase in affinity of hSK1 with vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol. Mutants T54A and N89A lose selective binding to POPC/POPS over POPC/POPG, whereas the S168A mutant maintain the selectivity shown by WT
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brenda
additional information
-
subcellular localization depends on the tissue type
-
brenda
additional information
unlike isozyme SK1, isozyme SK2 does not translocate the membrane fraction following calmodulin binding
-
brenda
additional information
unlike isozyme SK1, isozyme SK2 does not translocate the membrane fraction following calmodulin binding
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brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
activation-dependent increase of intracellular Ca2+ concentration, degranulation (release of alpha and dense granules), integrin alphaIIbbeta3 activation, and aggregation are all significantly increased in enzyme-deficient sphk1-/- platelets compared with wild-type sphk1+/+ platelets. While platelet adhesion and thrombus formation under arterial shear rates are significantly augmented in Sphk1-deficient platelets, bleeding time and blood count are unaffected in sphk1-/- mice
malfunction
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme
malfunction
dysregulation of the sphingosine-1-phosphate pathway is linked to a number of immune system disorders
malfunction
loss of sphingosine kinase 1 potentiates induction of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted, also known as CCL5) in HeLa cells stimulated with TNF-alpha despite RANTES induction being highly dependent on the NF-kappaB pathway. Analysis of the mechanism by which SK1 regulates RANTES induction, overview. Loss of SK1 strongly upregulates RANTES independently of effects on NF-kappaB activation, while loss of SK2 does not affect NF-kappaB pathway activation
malfunction
single SK1 and SK2 knockout mouse models show little phenotypic change
malfunction
-
genetic deficiency of isoform sphk-1 in the intestine inhibits activation of the mitochondrial unfolded protein response
malfunction
isoform SPHK1 deletion reduces endoplasm reticulum stress and alleviates inflammation response in hydrogen peroxide-treated cells
malfunction
sphingosine kinase-1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell infiltration
malfunction
-
activation-dependent increase of intracellular Ca2+ concentration, degranulation (release of alpha and dense granules), integrin alphaIIbbeta3 activation, and aggregation are all significantly increased in enzyme-deficient sphk1-/- platelets compared with wild-type sphk1+/+ platelets. While platelet adhesion and thrombus formation under arterial shear rates are significantly augmented in Sphk1-deficient platelets, bleeding time and blood count are unaffected in sphk1-/- mice
-
malfunction
-
genetic deficiency of isoform sphk-1 in the intestine inhibits activation of the mitochondrial unfolded protein response
-
metabolism
the interconversion of sphingosine and sphingosine 1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
metabolism
the interconversion of sphingosine and sphingosine1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
metabolism
the interconversion of sphingosine and sphingosine1-phosphate is mediated in the forward direction by sphingosine kinase and in the opposing way by specific sphingosine 1-phosphate phosphatases and less specific lipid phosphate phosphatases
physiological function
-
a short period of ischaemic postconditioning protects wild-type mouse hearts against ischaemia/reperfusion injury. The cardiac protection induced by postcondition is abrogated in SphK1-KO mouse hearts
physiological function
-
activation of Gq protein-coupled receptors induces a profound, rapid and long-lasting translocation of isoform SphK1 to the plasma membrane. Classical Gq signalling pathways, or phosphorylation at Ser225, phospholipase D and Ca2+/calmodulin are not involved in M3 receptor-induced SphK1 translocation in HEK-293 cells. Translocation is associated with Sphingosine 1-phosphate receptor internalization, which is dependent on catalytic activity of SphK1 and sphingosine 1-phosphate receptor binding and thus results from S1P receptor cross-activation
physiological function
-
adenovirus-mediated SPK1 gene transfer to rat mesothelial cells increases the cellular SPK1 activity, and leads to enhanced migration. Median adhesion scores are significantly lower in the transfected group than in controls in both rat caecum and rat uterine horn models
physiological function
-
adiponectin-induced COX-2 expression is reduced by treatment with a sphingosine kinase-1 inhibitor or siRNA targeting SphK-1. Treatment with a sphingosine-1-phosphate receptor antagonist also diminishes COX-2 expression in response to adiponectin stimulation
physiological function
-
cell lines sensitive to daunorubicin show increased ceramide content, while cell lines resistant to daunorubicin do not when treated with low doses of drug. Upon daunorubicin treatment, sphinganine 1-phosphate decreases more in the sensitive cell lines than in the resistant cell lines. A sphinganine kinase inhibitor recovers the daunorubicin sensitivity of daunorubicin resistant cells. The modulation of isoform Sk1 gene expression by overexpression or using siRNA affects the daunorubicin sensitivity of cell lines
physiological function
-
depletion of isoform Sk1 by siRNA or inhibitors leads to accelerated connective tissue growth factor CTGF induction, mediated by sphingosine 1-phosphate
physiological function
-
endothelial cells overepressing isoform Sk1 show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption
physiological function
-
filamin A links SphK1 and S1P1 receptor to locally influence the dynamics of actin cytoskeletal structures by orchestrating the concerted actions of of SphK1, FLNa, and PAK1, each of which requires and/or regulates the actions of the others, at lamellipodia to promote cell movement
physiological function
-
HUVEC cells with 3- to 5fold overexpression of isoform SK1 show an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells show constitutive activation, and a more augmented vascular cell adhesion molecule VCAM-1 and E selectin response to TNF compared with empty vector control cells
physiological function
-
in a murine collagen-induced arthritis model, prophylactic i.p. administration of SphK1 siRNA significantly reduces the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulates serum levels of sphingosine 1-phosphate, IL-6, TNF-alpha, IFN-gamma, and IgG2a anticollagen Ab. Ex vivo analysis demonstrates significant suppression of collagen-specific proinflammatory/Th1 cytokine IL-6, TNF-alpha, IFN-gamma release in SphK siRNA-treated mice. Mice received with SphK2 siRNA develop more aggressive disease, higher serum levels of IL-6, TNF-alpha, and IFN-gamma, and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients
physiological function
-
in cardiac fibroblasts, sphingosine 1-phosphate increases alpha-smooth muscle actin and collagen expression in a S1P2 receptor- and Rho-kinase-dependent manner. TGF-beta increases sphingosine kinase 1 expression and activity. TGF-beta-stimulated collagen production is inhibited by SphK1 or S1P2 siRNA, a SphK inhibitor, and an anti-S1P monoclonal antibody
physiological function
-
in contrast to wild-type mice, Sphk1-/- mice show markedly enhanced pulmonary edema formation in response to lipopolysaccharide and PAR-1 activation. Increased SPHK1 activity and decreased intracellular S1P concentration precede the onset of lung microvascular barrier recovery. Knockdown of SPHK1 decreases basal sphingosine 1-phoshate production and Rac1 activity but increases basal endothelial permeability. In SPHK1-depleted cells, PAR-1 activation fails to induce Rac1 activation but augments RhoA activation and endothelial hyperpermeability response. Knockdown of S1P1 receptor in endothelial cells also enhances the increase in endothelial permeability following PAR-1 activation. Sphingosine 1-phosphate treatment of Sphk1-/- lungs or SPHK1-deficient endothelial cells restores endothelial barrier function
physiological function
-
in SPHK1-deficient mice, absence of the enzyme abrogates MCP-1 production induced in dermal microvascular endothelial cells upon treatment with thrombin or PAR-1 activating peptide
physiological function
-
inhibition of isoform Sk1 or the ATP-binding cassette ABCC1 multidrug transporter attenuates calcium entry to cells, the addition of exogenous sphingosine 1-phosphate restores calcium entry. Overexpression of wild-type isoform Sk1, but not sk2, enhances phosphatese inhibitor calyculin-evoked calcium entry, whereas calcium entry is decreased in cells transfected with the dominant-negative G82D Sk1 mutant
physiological function
-
isoform Sk1 activity is causally associated with endocrine resistance in MCF-7 cells. Enforced overexpression of Sk1 results in enhanced cell proliferation and resistance to tamoxifen-induced cell growth arrest and apoptosis. Tamoxifen-resistant cells exhibit higher levels of Sk1 expression and activity. Inhibition of Sk1 by pharmaceutical inhibitors or the dominant-negative mutant G82D restores the antiproliferative and proapoptotic effect of tamoxifen. Silencing of isoform Sk1, but not Sk2, expression by siRNA also restores the tamoxifen responsiveness in the resistant cells
physiological function
-
isoform Sk1 interacts with four-and-a-half LIM only protein FHL-2. Overexpression of FHL-2 in endothelial cells inhibits VEGF-induced Sk1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. Overexpression of FHL-2 has no effect on sphinganine 1-phosphate induced Akt phosphorylation. VEGF stimulation decreases the binding of FHL-2 and Sk1. Depletion of FHL-2 by siRNA increases endothelial cell migration accompanied with Sk1 and Akt activation
physiological function
-
isoform SphK1 deficient SphK1-/- mice are much more susceptible to lipopolysaccharide-induced lung injury than wild-type. Overexpression of wild-type SphK1 in lungs protects SphK1-/- mice from lung injury and attenuates the severity of the response to lipopolysaccharide. Overexpression of a ShpK1 kinase-dead mutant in SphK1-/- mouse lungs further exacerbates the response to lipopolysaccharide as well as the extent of lung injury. Wild-type isoform SphK2 overexpression also fails to provide protection and augments the degree of lipopolysaccharide-induced lung injury
physiological function
-
knock-down of SK1 using siRNA is able to inhibit the TNF but not the lipopolysaccharide inflammatory response. Knock-down of SK1 enhances both TNF- and lipopolysaccharide-induced apoptosis
physiological function
-
knockdown of SK1 expression by specific siRNA inhibits 11,12-epoxyeicosatrienoic acid-induced endothelial cell proliferation and migration, whereas SK2 siRNA knockdown is without effect
physiological function
-
mice depleted of isoform SK1 have increased vascular leakiness, whereas mice transgenic for SK1 in endothelial cells show attenuation of leakiness
physiological function
-
overexpression of isoform Sk1 in ML-1 cells results in increased expression of sphingosine 1-phosphate, which can be attenuated by inhibiting Sk1 activity and an ATP-binding cassette transporter. Overexpression of Sk1 enhances serum-induced migration of ML-1 cells. Inhibition of protein kinase Calpha attenuates migration in Sk1 overexpressing cells. Overexpressing cells show an impaired adhesion, slower cell growth, and up-regulation of ERK1/2 phosphorylation
physiological function
-
overexpression of SK1 results in inhibition of permeability similar to that seen for Ang-1, which rapidly and transiently stimulates SK1 activity and phosphorylation, and induces an increase in intracellular sphingosine 1-phosphate concentration. Knockdown of SK1 by siRNA blocks Ang-1-mediated inhibition of permeability. Transfection with S225A, a nonphosphorylatable mutant of SK1, inhibits basal leakiness, and both S225A and a dominant-negative SK1 mutant remove the capacity of Ang-1 to inhibit endotheial cell permeability. These effects are independent of extracellular sphingosine 1-phosphate
physiological function
-
short-term androgen removal induces a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that is not observed in the hormone-insensitive PC-3 cells. The addition of dihydrotestosterone to androgen-deprived LNCaP cells re-establishes cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 can markedly impede the effects of dihydrotestosterone. Long-term removal of androgen support in LNCaP and C4-2B cells results in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which is characterized by the acquisition of a neuroendocrine-like cell phenotype. Inhibition of the PI3K/Akt pathway by negatively impacting SphK1 activity can prevent neuroendocrine differentiation in both cell models, an event that can be mimicked by SphK1 inhibitors
physiological function
-
siRNA of SPHK1 inhibits cell proliferation of v-Src-transformed NIH-3T3 cells
physiological function
-
SK1-/- mice treated with dextran sulfate sodium have significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than wild-type mice. SK1-/- mice have no systemic inflammatory response, and wild-type but not SK1-/- mice treated with dextran sulfate sodium have significant increases in blood sphingosine 1-phosphate levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike wild-type mice, SK1-/- mice fail to show colonic COX-2 induction despite an exaggerated TNF-alpha response
physiological function
-
SphK activity, SphK1 protein content and sphingosine 1-phosphate formation are enhanced in myoblasts that became confluent as well as in differentiating cells. Enforced expression of SphK1 reduces the myoblast proliferation rate, enhances the expression of myogenic differentiation markers and anticipates the onset of differentiated muscle phenotype. Down-regulation of SphK1 by specific silencing byRNA interference or overexpression of a catalytically inactive SphK1, significantly increases cell growth and delays the beginning of myogenesis. Exogenous addition of sphingosine 1-phosphate rescues the biological processes. Stimulation of myogenesis in SphK1-overexpressing myoblasts is abrogated by treatment with short interfering RNA specific for S1P2 receptor
physiological function
-
SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1alpha levels is mediated by the Akt/glycogen synthase kinase-3beta signaling pathway that prevents its von Hippel-Lindau proteinmediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1A and its transcriptional activity in several human cancer cell lineages from prostate, brain, breast, kidney, and lung, suggesting a canonical pathway
physiological function
-
SphK1 enforced expression in PC-3 and LNCaP cells shifts the lipid biostat toward prosurvival sphingosine 1-phosphate and protects against B-5354cinduced apoptosis
physiological function
-
SphK1 siRNA reduces both the SphK1 mRNA and the protein levels by 70% and has no effect on SphK2 expression. The SphK2 siRNA is equally specific but somewhat less efficient at reducing SphK2 expression. Decreasing SphK1expression significantly decreases both TGFbeta-induced chemotactic migration and invasion, whereas decreasing SphK2 expression inhibits chemotactic migration less effectively and has no effect on chemotactic invasion. Decreased expression of SphKs also inhibits TGFbeta activation of ERK1/2. TGFbeta activation of sphingosine kinases and formation of sphinmgosine 1-phosphate contribute to non-Smad signaling
physiological function
-
SphK1-/- mice subjected to azoxymethane treatment have significantly less aberrant crypt foci formation and significantly reduced colon cancer development than wild-type
physiological function
-
SPHK1-transgenic mice overexpress SPHK1 in diverse tissues, with a nearly 20fold increase in enzymatic activity. The transgenic mice grow normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Transgenic mice with high but not low expression levels of SPHK1 develop progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile transgenic mice with pitavastatin, or deletion of S1P3, a major myocardial S1P receptor subtype both inhibit cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, also inhibits cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct is 30% decreased in SPHK1-transgenic mice compared with wild-type mice
physiological function
-
stimulation of the lung epithelial cell line A-549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine 1-phosphate, abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin. PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells is also dependent on SPHK1
physiological function
-
suppression of SphK1 by its inhibitor, N,N-dimethylsphingosine, or siRNA results in decreased mRNA expression of TNF-alpha, IL-1beta and iNOS and release of TNF-alpha and nitric oxide in lipopolysaccharid-activated microglia
physiological function
-
the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors is comparable. Tumor-associated macrophages from SphK2-deficient tumors display a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206
physiological function
-
the knockdown of SphK1 by siRNA in mast cells inhibits several signaling mechanisms and effector functions, triggered by FcepsilonRI stimulation and including Ca2+ signals, NFkappaB activation, degranulation, cytokine/chemokine, and eicosanoid production. Silencing SphK2 has no effect at all. Silencing SPHK1 in vivo, in different strains of mice, strongly inhibits mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 has no effect and the mice develop anaphylaxis. In mast cells derived from SPHK1-/- and SPHK2-/- mice, the calcium response and degranulation, triggered by FcepsilonRI-cross-linking, is not different from that triggered in wild-type cells. IgE-mediated anaphylaxis in the knockout mice shows similar levels in temperature changes and serum histamine to that from wild-type mice
physiological function
-
translocation and precise subcellular positioning of Sk1 is essential for full function, and two distinct sphingosin 1-phosphate pools, intra- and extracellular, contribute to the maintenance of vascular tone
physiological function
-
under basal conditions, SK1, integrin alphaVbeta3 and CD31 exist as a heterotrimeric complex. Under conditions that affect endothelial cell survival such as loss of contact with the extracellular matrix or growth factor activation, more of this heterotrimeric complex forms. Increased heterotrimeric complex formation requires SK1 phosphorylation at serine 225 for, activation of integrin alphaVbeta3, and endothelial cell survival signals, including Bcl-X and nuclear factor-B pathways. beta3-Integrin depletion confirms the requirement for this heterotrimeric complex in SK1-mediated endothelial cell survival
physiological function
-
under hypoxia, isoform Sk2 shows an increase in protein level and activity, which correlates with the release of shingosine 1-phosphate into the medium. Knockdown of Sk2 by siRNA releives chemoresistance of A-450 cells under hypoxia and conditioned medium obtained from Sk2 knock-down cells is only partly protective, while conditioned medium of cells with normal levels of Sk2, incubated for 24 h under hypoxia, protects naive A-549 cells from etoposide-induced cell death
physiological function
-
when sphingosine kinase 1 is deleted in Sandhoff disease mice, a prototypical neuronopathic lysosomal storage disorder, a milder disease course occurs, with decreased proliferation of glial cells and less-pronounced astrogliosis. A similar result of milder disease course and reduced astroglial proliferation is obtained by deletion of the gene for the S1P(3) receptor, a G protein-coupled receptor enriched in astrocytes
physiological function
-
wild-type mesangial cells respond to staurosporine with increased DNA fragmentation and caspase-3 processing, which is enhanced in SK1-/- cells. SK2-/- cells are highly resistant to staurosporine-induced apoptosis. The basal phosphorylation and activity of the anti-apoptotic protein kinase B and of its substrate Bad are decreased in SK1-/- but not in SK2-/- cells. Upon staurosporine treatment, phosphorylation of protein kinase B and Bad decrease in wild-type and SK1-/- cells, but remain high in SK2-/- cells. The anti-apoptotic Bcl-XL is significantly upregulated in SK2-/- cells
physiological function
-
application of siRNA-SPHK1 and sphingosine kinase inhibitor effectively blocks the expression of hypoxia inducible factor 1alpha, phospho-AKT and vascular endothelial growth factor production in PC-3 cells under hypoxia
physiological function
expression of isoform SK1 artificially targeted to the endoplasmic reticulum or without targeting signal, but surprisingly not plasma membrane-targeted SK1, results in a dramatic increase in the phosphorylation of dihydrosphingosine. Knockdown of endogenous SK1 diminishes both dihydrosphingosine-1-phosphate and sphinganine 1-phosphate levels. Sphinganine 1-phosphate produced at the plasma membrane is degraded to the same extent as that produced in the endoplasmic reticulum indicating that there is an efficient mechanism for the transport of sphinganine 1-phosphate. Sphinganine 1-phosphate degradation is primarily driven by lyase cleavage of sphinganine 1-phosphate
physiological function
-
mice with kidney-specific overexpression of enhanced green fluorescent protein fused to isoform SK1 have significantly improved renal function with lower plasma creatinine, renal necrosis, apoptosis, and inflammation. Overexpression of the fusion protein cultured human proximal tubule cells protects against peroxide-induced necrosis. Selective overexpression of the construct leads to increased HSP27 mRNA and protein expression in vivo and in vitro. Functional protection as well as induction of HSP27 with the construct overexpression in vivo is blocked with sphingosine-1-phosphate-1 receptor-1 antagonism
physiological function
-
renal ischemia-reperfusion injury induces isoform SK1, but not SK2, in the kidneys. Knockout or pharmacological inhibition of isoform SK1 increases injury after renal ischemia-reperfusion injury
physiological function
D-erythro-sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
isozymes sphingosine kinases 1 and 2 (SK1 and SK2) generate the bioactive lipid mediator sphingosine 1-phosphate and as such play a significant role in cell fate and in human health and disease, SK1 and SK2 have overlapping, yet in some cases opposing, effects, overview. D-erythro-Sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors
physiological function
lipid kinase sphingosine kinase 1 catalyzes the conversion of sphingosine to sphingosine-1-phosphate, which plays a role in lymphocyte trafficking, angiogenesis, and response to apoptotic stimuli. As a central enzyme in modulating the sphingosine-1-phosphate levels in cells, the enzyme is an important regulator for diverse cellular functions
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2
physiological function
sphingosine 1-phosphate is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2. Isozyme SphK2 can localize in the nucleus to inhibit DNA synthesis and regulate HDAC1/2 activity
physiological function
sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation. In mast cells, intracellular Ca2+ is rapidly and transiently increased by spingosine kinase 1. Sphingosine 1-phosphate mobilizes intracellular Ca2+ in mast cells in an inositol triphosphate-dependent manner. In other cell types, sphingosine kinases regulate intracellular Ca2+ by influencing voltage-gated Ca2+ channels or by activating the store-operated calcium entry. Sphingosine kinases and sphingosine 1-phosphate further regulate platelet formation by megakaryopoiesis. They are effective by upregulating Src family kinases in megakaryocytes. Megakyocytes express the S1P multifunctional receptor S1pr1, and S1P signaling is an important prerequisite for proper thrombopoesis
physiological function
sphingosine kinase 1 produces the pro-survival sphingolipid sphingosine 1-phosphate and is implicated in inflammation, proliferation, and angiogenesis. The enzyme is required for activation of p38 MAPK, but is not required for transcriptional NF-kappaB activity following TNF treatment. But nuclear translocation of NF-kappaB subunits does not require enzyme SK1
physiological function
sphingosine-1-phosphate is a lipid second messenger formed upon phosphorylation of sphingosine by sphingosine kinase and plays a crucial role in natural killer cell proliferation, migration, and cytotoxicity
physiological function
isofom SPHK1 upregulation, induced by hydrogen peroxide, is responsible for cerebral IR injury through inducing endoplasm reticulum stress and inflammation response in a manner working through the nuclear factor-kappaB signaling pathway
physiological function
-
isoform SPHK-1 activates the mitochondrial unfolded protein response
physiological function
sphingosine kinase-1 is a key regulator of anti-tumor immunity. Increased expression of the enzyme in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-programmed cell death protein-1
physiological function
the enzyme regulates the expression of interleukin-17A in activated microglia in cerebral ischemia/reperfusion
physiological function
-
sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation. In mast cells, intracellular Ca2+ is rapidly and transiently increased by spingosine kinase 1. Sphingosine 1-phosphate mobilizes intracellular Ca2+ in mast cells in an inositol triphosphate-dependent manner. In other cell types, sphingosine kinases regulate intracellular Ca2+ by influencing voltage-gated Ca2+ channels or by activating the store-operated calcium entry. Sphingosine kinases and sphingosine 1-phosphate further regulate platelet formation by megakaryopoiesis. They are effective by upregulating Src family kinases in megakaryocytes. Megakyocytes express the S1P multifunctional receptor S1pr1, and S1P signaling is an important prerequisite for proper thrombopoesis
-
physiological function
-
isoform SPHK-1 activates the mitochondrial unfolded protein response
-
additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, residues G79, G80, G82, and K103 are important. Sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2
additional information
modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
-
modeling of the catalytic mechanism, overview. Residue Asp81 plays a critical role in the phosphoryl transfer step, but not in the binding of ATP
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1
additional information
schematic model of the proposed mechanism of the phosphorylation of D-erythro-sphingosine catalyzed by isozyme SK1
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LCB4_SCHPO
Schizosaccharomyces pombe (strain 972 / ATCC 24843)
458
0
51289
Swiss-Prot
other Location (Reliability: 1)
LCB4_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
624
0
69639
Swiss-Prot
other Location (Reliability: 4)
LCB5_YEAST
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
687
0
77566
Swiss-Prot
other Location (Reliability: 5)
SPHK1_ARATH
485
0
53699
Swiss-Prot
other Location (Reliability: 3)
SPHK1_CAEEL
473
0
52453
Swiss-Prot
other Location (Reliability: 4)
SPHK1_HUMAN
384
0
42518
Swiss-Prot
Mitochondrion (Reliability: 5)
SPHK1_MOUSE
382
0
42443
Swiss-Prot
other Location (Reliability: 5)
SPHK1_RAT
383
0
42418
Swiss-Prot
Mitochondrion (Reliability: 4)
SPHK2_ARATH
481
0
53890
Swiss-Prot
other Location (Reliability: 5)
SPHK2_HUMAN
654
0
69217
Swiss-Prot
other Location (Reliability: 1)
SPHK2_MOUSE
617
0
65618
Swiss-Prot
other Location (Reliability: 3)
SPHKA_DICDI
624
0
70024
Swiss-Prot
other Location (Reliability: 2)
SPHKB_DICDI
760
0
83966
Swiss-Prot
other Location (Reliability: 1)
A0A8J5EJW9_9ASCO
476
0
52024
TrEMBL
other Location (Reliability: 4)
A0A1Z5KJ54_FISSO
498
0
55219
TrEMBL
other Location (Reliability: 1)
A0A2P6Q3Z0_ROSCH
345
0
37895
TrEMBL
other Location (Reliability: 2)
U4KJN3_ALTPJ
Alteracholeplasma palmae (strain ATCC 49389 / J233)
304
0
34712
TrEMBL
-
A0A3Q8IGX7_LEIDO
935
0
100869
TrEMBL
Mitochondrion (Reliability: 3)
A0A8J5BJT1_9ASCO
329
0
35888
TrEMBL
other Location (Reliability: 1)
A0A0B2NX89_GLYSO
486
0
53583
TrEMBL
other Location (Reliability: 2)
A0A8J5DZ26_9ASCO
462
0
50476
TrEMBL
other Location (Reliability: 2)
A0A8J5BW76_9ASCO
477
0
52104
TrEMBL
other Location (Reliability: 5)
A0A0F8B3B3_CERFI
343
0
37206
TrEMBL
Mitochondrion (Reliability: 5)
A0A8J5BPN7_9ASCO
463
0
50534
TrEMBL
other Location (Reliability: 4)
G0QVG8_ICHMG
Ichthyophthirius multifiliis (strain G5)
886
0
100604
TrEMBL
other Location (Reliability: 3)
A0A5B7CAY6_DAVIN
239
0
26142
TrEMBL
Chloroplast (Reliability: 4)
Q4Q9C3_LEIMA
935
0
101018
TrEMBL
Mitochondrion (Reliability: 3)
Q28EJ9_XENTR
509
0
55559
TrEMBL
other Location (Reliability: 2)
A0A088RTA0_9TRYP
817
0
90375
TrEMBL
other Location (Reliability: 2)
A0A7R8CG35_LEPSM
559
0
63242
TrEMBL
other Location (Reliability: 1)
A0A072V3V9_MEDTR
484
0
53501
TrEMBL
other Location (Reliability: 3)
A0A2P6Q3L7_ROSCH
493
0
54013
TrEMBL
other Location (Reliability: 4)
A0A0B2PIE9_GLYSO
131
0
13946
TrEMBL
other Location (Reliability: 2)
A0A2I0A3T1_9ASPA
758
0
83620
TrEMBL
Mitochondrion (Reliability: 4)
A0A812DR79_SEPPH
455
3
52267
TrEMBL
other Location (Reliability: 3)
Q5U4T6_XENLA
509
0
55999
TrEMBL
other Location (Reliability: 2)
A0A5B6ZJ96_DAVIN
193
0
21326
TrEMBL
other Location (Reliability: 4)
A0A2G9GZW6_9LAMI
497
0
55119
TrEMBL
other Location (Reliability: 1)
A0A6J8ATU9_MYTCO
617
0
69295
TrEMBL
other Location (Reliability: 2)
A0A1G4I5S9_TRYEQ
769
0
83520
TrEMBL
other Location (Reliability: 2)
K0KIN6_WICCF
Wickerhamomyces ciferrii (strain ATCC 14091 / BCRC 22168 / CBS 111 / JCM 3599 / NBRC 0793 / NRRL Y-1031 F-60-10)
509
0
56112
TrEMBL
other Location (Reliability: 2)
A4HES6_LEIBR
817
0
90435
TrEMBL
other Location (Reliability: 2)
A4I203_LEIIN
935
0
100835
TrEMBL
Mitochondrion (Reliability: 3)
A0A8J5BEB9_9ASCO
330
0
36026
TrEMBL
other Location (Reliability: 1)
M5BI27_THACB
Thanatephorus cucumeris (strain AG1-IB / isolate 7/3/14)
341
0
37251
TrEMBL
other Location (Reliability: 3)
A0A072U6E3_MEDTR
777
0
85162
TrEMBL
Chloroplast (Reliability: 3)
A0A2P6R4W1_ROSCH
765
0
83573
TrEMBL
Mitochondrion (Reliability: 5)
A0A1Z5KSZ0_FISSO
496
0
54939
TrEMBL
other Location (Reliability: 1)
A0A8B6FYR6_MYTGA
616
0
68979
TrEMBL
other Location (Reliability: 2)
A0A3G2S6H3_9BASI
538
0
58830
TrEMBL
other Location (Reliability: 4)
O88885_MOUSE
504
0
55119
TrEMBL
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
43000
49000
additional information
additional information
lesser amounts of immunoreactive protein migrate in the 45-48 kDa range
additional information
lesser amounts of immunoreactive protein migrate in the 45-48 kDa range
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
additional information
additional information
-
relationship to diacylglyceride kinases, NAD+ kinases and 6-phosphofructokinases
additional information
-
structure analysis of the 2 isozymes, schematic map, the enzyme contains 5 sequences stretches C1-C5 typical for lipid kinases, but the enzyme does not contain distinct domains for catalysis or substrate binding, overview
additional information
-
isoform Sk1 interacts with four-and-a-half LIM only protein FHL-2. Overexpression of FHL-2 in endothelial cells inhibits VEGF-induced Sk1 activity, phosphatidylinositol 3-kinase activity, and phosphorylation of Akt and eNOS. Overexpression of FHL-2 has no effect on sphinganine 1-phosphate induced Akt phosphorylation. VEGF stimulation decreases the binding of FHL-2 and Sk1. Depletion of FHL-2 by siRNA increases endothelial cell migration accompanied with Sk1 and Akt activation
additional information
-
isoform SK1 interacts with subunit 7 of cytosolic chaperonin CCT, i.e. chaperonin containing t-complex polypeptide, also called TRiC for TCP-1 ring complex, a hexadecameric chaperonin that binds unfolded polypeptides. Other CCT/TRiC subunits also associate with SK1 in HEK293T cell lysates in an ATP-sensitive manner. CCT/TRiC binds specifically to newly translated SK1. Depletion of functional CCT/TRiC through the use of RNA interference in HeLa cells or temperature sensitive CCT mutants reduces cellular SK1 activity
additional information
oligomeric protein containing noncooperative catalytic sites, the allosteric site exerts an autoinhibition of the catalytic site
additional information
the SphK1 structure reveals a two-domain architecture in which its catalytic site is located in the cleft between the two domains and a hydrophobic lipid-binding pocket is buried in the C-terminal domain, structure comparisons with Staphylococcus aureus DgkB, PDB ID 2QVL, and Archaeoglobus fulgidus NAD kinase, PDB ID 1ZOZ
additional information
-
the SphK1 structure reveals a two-domain architecture in which its catalytic site is located in the cleft between the two domains and a hydrophobic lipid-binding pocket is buried in the C-terminal domain, structure comparisons with Staphylococcus aureus DgkB, PDB ID 2QVL, and Archaeoglobus fulgidus NAD kinase, PDB ID 1ZOZ
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
isozyme SPHK1 is phosphorylated at Ser225 by extracellular signal-regulated kinases 1 and 2, i.e. ERK1 and 2, and by cyclin dependent kinase 2, i.e. CDK2, recombinant isozyme SPHK1 in HEK293 cells is phosphorylated by ERK1 after stimulation with TNF-alpha, mechanism, overview, phosphorylation activates the enzyme by up to 14fold
phosphoprotein
isozyme SphK1 migrates to the plasma membrane upon phosphorylation
phosphoprotein
phosphorylation of S225 results in a 14fold increase in SK1 activity arising from a 13.6fold increase in kcat
phosphoprotein
the enzyme is phosphorylated and activated mainly by proline-rich receptor-like protein kinase 2
phosphoprotein
the translocation and activity of isoform SphK1 are regulated by its phosphorylation of Ser225
phosphoprotein
-
in muscle resistance artery, pressure-dependent activation and translocation of isoform Sk1 by ERK1/2 is critically dependent on its serine225 phosphorylation site
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
homology modeling based of Staphylococcus aureus diacylglycerol kinase, PDB entry 2QV7, and docking of substrate sphinganine 1-phosphatre to the model con taining bound ADP
purified recombinant truncated enzyme comprising residues 9-364, in apo-form and in complex with inhibitor SKI-II, and with inhibitor SKI-II and ADP, sitting drop vapour diffusion method, mixing of 0.001 ml of 10 mg/ml protein in 50 mM Tris-HCl, pH 8.5, 300 mM NaCl, 0.5 M GdnHCl, 10% glycerol, 0.1% Tween 20, and 10 mM DTT, and for complex crystals with a 3fold excess of inhibitor, and ATP/ADP, with 0.001 ml of well solution containing 1.0-1.4 M ammonium sulfate, 0.3-1.3 M NaCl, and 0.1 M Bis-Tris, pH 6.0, 16°C, X-ray diffraction structure determination and analysis at 2.0-2.3 A resolution, molecular replacement
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D176N
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
D176N/D178N
site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type
D176N/E180Q
site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type
D81A
site-directed mutagenesis, the mutant shows essentially no activity for phosphoryl transfer and ADP formation
D81N
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
D89A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane
E180Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
E182Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
F197A
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
F197A/L198Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
F303H
G111A
site-directed mutagenesis, the mutant is catalytically inactive
G111D
site-directed mutagenesis, the mutant is catalytically inactive
G113A
G113D
site-directed mutagenesis, the mutant is catalytically inactive
G212E
site-directed mutagenesis, the mutant is catalytically inactive
G212E/L218A
site-directed mutagenesis, the mutant is catalytically inactive
G26A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
G26D
site-directed mutagenesis, the mutant is catalytically inactive
G80A
site-directed mutagenesis, the mutant is catalytically inactive
G80D
site-directed mutagenesis, the mutant is catalytically inactive
G82A
site-directed mutagenesis, the mutant shows a 44.7fold increase in Km compared to the wild-type
G82D
H122A
the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 60%
K103A
site-directed mutagenesis, the mutant is catalytically inactive
K103R
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
K27A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
K29A
site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type
L134Q
L147Q
L153Q
L187Q
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
L194Q
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
L198Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
L200Q
L218A
site-directed mutagenesis, the mutant shows about 38% of wild-type activity
N121E
the mutation reduces cleavage by cathepsin B at the mutation site, reduced activity by 20%
N89A
site-directed mutagenesis, the mutant loses 50% activity compared to the wild-type, and loses selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol
R185A/R186A
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
R56A/R57A/H59A/R61A
the mutations of isoform SphK1 reduce the phorbol 12-myristate 13-acetate- and ceramide 1-phosphate-induced translocation of isoform SphK1 to the plasma membrane, however, the capacity of ceramide 1-phosphate to bind with and activate isoform SphK1 is not affected by the mutations
S168A
site-directed mutagenesis, the mutant maintains the selectivity of selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol, as shown by the wild-type
S225A
S225D
site-directed mutagenesis, mutation of S225 to aspartic and glutamic acids, mimicing serine phosphorylation, does not alter SK1 activity but maintains preferred binding of SK1 to plasma membrane over nuclear membrane
S225E
site-directed mutagenesis, mutation of S225 to aspartic and glutamic acids, mimicing serine phosphorylation, does not alter SK1 activity but maintains preferred binding of SK1 to plasma membrane over nuclear membrane
S351A
site-directed mutagenesis, the mutant shows about 115% of wild-type activity
S401A
site-directed mutagenesis, the mutant shows about 109% of wild-type activity
S430A
site-directed mutagenesis, the mutant shows about 124% of wild-type activity
S441A
site-directed mutagenesis, the mutant shows about 35% of wild-type activity
S79A
site-directed mutagenesis, the mutant shows a 1.5fold increase in Km compared to the wild-type
S79D
site-directed mutagenesis, the mutant is catalytically inactive
T54A
T578A
site-directed mutagenesis, the mutant shows about 56% of wild-type activity
T74A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane
V290N
V327A/L328Q
site-directed mutagenesis, the mutant shows about 75% of wild-type activity
S225A
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expression in resistance artery smooth muscle cells reduces resting and myogenic tone, resting Ca2+, pressure-induced Ca2+ elevations, and Ca2+ sensitivity. Lack of function of S225A can only partly be overcome by forced localization to the plasma membrane
D175N/D177N
site-directed mutagenesis, less than 5% of wild-type enzyme activity
D177N
site-directed mutagenesis, less than 10% of wild-type enzyme activity
G213E/L219A
site-directed mutagenesis, the mutant is catalytically inactive
G82D
L219A
site-directed mutagenesis, the mutant shows about 38% of wild-type activity
S225A
the mutation prevents ERK1/2-mediated phosphorylation and membrane localization of SK1
G82D
-
dominant-negative mutant, calcium entry to cells is decreased in mutant lines. Exogenous sphingosine 1-phosphate restores calcium entry
H122Y
no detectable difference in activity compared to the wild type enzyme
additional information
F303H
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
F303H
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
G113A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
G82D
-
dominant-negative SK1 mutant, removes the capacity of Ang-1 to inhibit endothelial cell permeability
G82D
-
dominant-negative SK1mutant, displays substantially attenuated 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoic acid-induced endothelial cell proliferation, migration, and tube formation in vitro and Matrigel plug angiogenesis in vivo
G82D
-
over-expression inhibits the TNF-induced vascular cell adhesion molecule VCAM-1 and E selectin and inhibits PMN adhesion
G82D
site-directed mutagenesis, the mutant is catalytically inactive
L134Q
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
L147Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
L147Q
site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type
L153Q
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
L153Q
site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type
L200Q
site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type
L200Q
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
S225A
the mutation prevents ERK1/2-mediated phosphorylation and membrane localization of SK1
S225A
-
transfection with S225A, a nonphosphorylatable mutant of SK1, inhibits basal leakiness, and both S225A and a dominant-negative SK1 mutant remove the capacity of Ang-1 to inhibit endothelial cell permeability
S225A
site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane, the mutant shows 39% reduced activity compared to the wild-type
T54A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type
T54A
site-directed mutagenesis, the mutant loses selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol
T54A
site-directed mutagenesis, the mutant shows 55% reduced activity compared to the wild-type
V290N
site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type
G82D
-
catalytically inactive. Overexpression in myoblast cells significantly increases cell growth and delays the beginning of myogenesis
additional information
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disruption mutants of genes sgkA and sgkB, single mutants with reduced activity, or double mutants nearly inactive, show increased sensitivity to the anticancer drug cisplatin and altered growth behaviour
additional information
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2
additional information
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2
additional information
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2, a Drosophila melanogaster null Sk2 transposon insertion mutant shows elevated long chain base levels, impaired flight performance, and diminished ovulation, phenotype analysis
additional information
complementation of yeast enzyme-deficient mutant strain by both Sk1 and Sk2, a Drosophila melanogaster null Sk2 transposon insertion mutant shows elevated long chain base levels, impaired flight performance, and diminished ovulation, phenotype analysis
additional information
deletion mutants in highly conserved regions, truncation mutants
additional information
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deletion mutants in highly conserved regions, truncation mutants
additional information
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isoform SphK2 contains a lipid binding domain at the N-terminal residues 1-175, a region of sequence that is absent in Sphk1. Deleting the N-terminal domain reduces Sphk2 membrane localisation in cells
additional information
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deletion of 21 amino acids from the COOH-terminus of isoform SphK1, expression of residues 1-363, results in about 2.2fold increase in catalytic activity relative to wild-type SphK1, which is independent of the phosphorylation state of Serine 225 and stimulation by phorbol-12,13-myristic acid. HEK-293 cells stably expressing the truncated protein exhibit enhanced cell growth under serum-deprived cell culture conditions. A further truncated mutant, residues 1-315, displays about 20% of wild-type activity
additional information
construction of an N- and C-terminally truncated enzyme form comprising residues 9-364 of full-length 368 residues, the mutant is catalytically active
additional information
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construction of an N- and C-terminally truncated enzyme form comprising residues 9-364 of full-length 368 residues, the mutant is catalytically active
additional information
construction of catalytically inactive deletion mutants DELTA1226 and DELTA226-619
additional information
construction of catalytically inactive deletion mutants DELTA1226 and DELTA226-619
additional information
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme. Deletion of 21 residues from the C-terminus (hSK1DELTA364-384) results in a protein that is constitutively and 2.2times more active than the wild-type. No significant change enzyme affinity for ATP but a slightly higher Vmax of 1.3fold are observed. Construction of mutations in domain 4 focusing primarily on SPH and calcium-calmodulin/CIB1 interactions
additional information
deletion of any one of the conserved domains hSK1DELTA17-36, hSK1DELTA72-96, hSK1DELTA107-119, hSK1DELTA165-198, or hSK1DELTA338-344 results in loss of interaction with calcium-loaded, sepharose-bound calmodulin, presumably due to improper protein folding, and sphingosine kinase activity. Truncation of the C-terminal 41 residues (hSK1DELTA344-384) also results in misfolded, inactive protein. In contrast, deletion of 17 residues (hSK1 DELTA368-384) yields a protein with affinity for calcium-calmodulin with activity equivalent to the wild-type enzyme. Deletion of 21 residues from the C-terminus (hSK1DELTA364-384) results in a protein that is constitutively and 2.2times more active than the wild-type. No significant change enzyme affinity for ATP but a slightly higher Vmax of 1.3fold are observed. Construction of mutations in domain 4 focusing primarily on SPH and calcium-calmodulin/CIB1 interactions
additional information
enzyme knockdown in HeLa cells using siRNA cell treatment. Enzyme knockdown significantly enhances RANTES induction in response to TNF with no statistically significant effect on unstimulated levels. RANTES induction is highly NF-kappaB-dependent as shown using NF-kappaB inhibitor BAY 11-7082
additional information
-
site-directed mutagenesis at Cys-4 and Cys-5 residues results in increased sphingosine kinase activity
additional information
site-directed mutagenesis at Cys-4 and Cys-5 residues results in increased sphingosine kinase activity
additional information
construction of catalytically inactive deletion mutants DELTA1-227 and DELTA227-618
additional information
construction of catalytically inactive deletion mutants DELTA1-227 and DELTA227-618
additional information
generation of enzyme-deficient sphk1-/- mice, platelets from sphk1-/- mice do not show spontaneous or activation-dependent formation of platelet-leukocyte aggregates and a significantly increased activation-dependent ATP release and in vitro thrombus formation compared with the wild-type
additional information
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generation of enzyme-deficient sphk1-/- mice, platelets from sphk1-/- mice do not show spontaneous or activation-dependent formation of platelet-leukocyte aggregates and a significantly increased activation-dependent ATP release and in vitro thrombus formation compared with the wild-type
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additional information
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spontaneous mutants with reduced enzyme activity
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
extensive dialysis or dilution in potassium phosphate buffer, 100 mM, pH 7.4, results especially during the early stages of purification in rapid loss of activity
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ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 100 mM phosphate buffer, pH 7.4, 1 mM 2-mercaptoethanol, 1 mM EDTA, 20% glycerol, stable for several months
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His6-tagged wild-type and mutant enzymes from High Five cells by nickel affinity chromatography, the tag is cleaved by TEV protease, followed by anion and cation exchange chromatographies, and gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloning and characterization of an isoform of rat SK1 with an N-terminal extension (long-rSK1). When the long-rSK1 is transfected in COS-7 cells, SK activity is 53fold increased. Substrate specificity and dependency on divalent cations of long-rSK1 are similar to those of rSK1
DNA and amino acid sequence determination and analysis
expression in HEK-293 cell
expression of FLAG-tagged isozyme in HEK293 cells, expression of His-tagged isozyme in Sf9 insect cells via baculovirus infection system
gene Sk1, DNA and amino acid sequence determination and analysis, 2 splicing variants, location on the X chromosome, functional overexpression of Sk1 in the yeast strain JSK398
gene Sk2, DNA and amino acid sequence determination and analysis, a single intron, location on chromosome 3, functional overexpression of Sk2 in the yeast strain JSK398
gene sphK1, sequence comparison of human isozymes sphingosine kinases 1 and 2
gene sphK2, sequence comparison of human isozymes sphingosine kinases 1 and 2
isoform SphK1 is expressed in Saccharomyces cerevisiae strain CGY32
isozymes SPHK1 and SPHK2, DNA and amino acid sequence determination and analysis
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isozymes SPHK1 and SPHK2, expression in HEK293 cells as EGFP-fusion proteins
isozymes SPHK1 and SPHK2, several splicing variants are differently active, expression in HEK293 cells as EGFP-fusion proteins
overexpression of gene sgkA leads to increased resistance to the anticancer drug cisplatin and altered growth behaviour
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overview
recombinant expression of N-terminally His6-tagged wild-type and mutant enzymes in High Five cells using the baculovirus transfection method
transient expression in murine C2C12 myoblasts in the cytosolic fraction, in Golgi-enriched and endosome/plasma membrane fraction of transfected cells, the over-expressed SphK1 is localized at plasma membrane, as well as at internal membranes, SphK1 partially colocalized with caveolin-1, known to be an integral plasma membrane protein, secretion of extracellularly produced sphingosine 1-phosphate
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
both lipopolysaccharide and thrombin increase mouse lung microvascular permeability and result in a delayed activation of SPHK1 that is coupled to the onset of restoration of pulmonary microvessel permeability
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dihydrotestosterone triggers cell growth in steroid-deprived MC-3T3 cells, associated with a rapid stimulation of isoform SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relies on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists can block SphK1 stimulation by dihydrotestosterone and its consequences. SphK1 inhibition also blocks cell proliferation, while ERK inhibition has no impact
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enzyme expression is increased in microglia subjected to oxygen-glucose deprivation
hypoxia increases SK1 mRNA levels, protein expression, and enzyme activity, followed by intracellular sphingosine 1-phosphate production and sphingosine 1-phosphate release. Knockdown of hypoxia-inducible factor HIF-2 by small interfering RNA abolishes the induction of SK1 and the production of extracellular shpingosine 1-phosphate after CoCl2 treatment, whereas HIF-1 small interfering RNA results in an increase of HIF-2 and of SK1 protein levels. HIF-2 binds the SK1 promoter
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in bronchial epithelial cells, SphK1 and MUC5AC expression is increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression is not changed. Inhibitor N,N-dimethylsphingosine decreases MUC5AC expression up-regulated by IL-13 treatment and inhibits IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation
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inhibition of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH2-terminal kinase inhibition suppresses SPHK1 expression in v-Src-transformed NIH-3T3 cells, whereas their overexpression increases SPHK1 mRNA. Modulation of AUF1 and HuR by their overexpression or siRNA reveals that SPHK1 mRNA in v-Src- and mock-NIH3T3 is regulated reciprocally by these factors
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isoform SPHK1 expression is significantly elevated after exposure to hydrogen peroxide
knockdown of isoform SK2 expression results in overexpression of isoform SK1 in several cell lines. Treatment with inhibitor (2S,3R,4E)-2-(dimethylamino)octadec-4-ene-1,3-diol triples the levels of isoform SK1 mRNA, but only slightly increases isoform SK2 expression. Treatment with inhibitor 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole increases mRNAs for both isoforms SK1 and SK2 by about 4fold
long-term removal of androgen support in LNCaP and C4-2B cells results in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which is characterized by the acquisition of a neuroendocrine-like cell phenotype
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sphingosine kinase-1 transcript levels are higher in human primary melanomas as compared to nevi
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
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the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells. IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines, it does not affect SphK2 expression. The IL-1-induced SphK1 up-regulation can be blocked by the inhibition of c-Jun N-terminal kinase, the overexpression of the dominant-negative c-Jun(TAM67), and the down-regulation of c-Jun expression by small interference RNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated via a novel AP-1 element located within the first intron of the sphk1 gene
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transforming growth factor TGF-beta2 activates the promoter of isoform Sk1, resulting in upregulation of its mRNa and protein expression
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treatment with inhibitors N,N-dimethylsphingosine or DL-threo-dihydrosphingosine or with doxorubicin leads to increase in expression as a result of apoptotic stress. The caspase inhibitor ZVAD reduces not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of sphingosine 1-phosphate
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treatment with lipopolysaccharid causes significantly enhances isoform SphK1 expression within 6 h, which declines back to baseline levels by 24 h. Expression of isoform SphK2 is gradually induced following lipopolysaccharide treatment and is elevated within 24 h
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treatment with lipopolysaccharide increases the SphK1 mRNA and protein expression in microglia leading to altered expression and production of proinflammatory cytokines and nitric oxide. Suppression of SphK1 by its inhibitor, N, N-dimethylsphingosine, or siRNA results in decreased mRNA expression of TNF-alpha, IL-1beta and iNOS and release of TNF-alpha and nitric oxide in lipopolysaccharid-activated microglia
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v-Src-transfected cells show both increased SPHK1 mRNA and enzyme activity. Inhibition of protein kinase C-alpha, signal transducers and activators of transcription 3 and c-Jun NH2-terminal kinase inhibition suppresses SPHK1 expression in v-Src-transformed NIH-3T3 cells, whereas their overexpression increases SPHK1 mRNA. Modulation of AUF1 and HuR by their overexpression or siRNA reveals that SPHK1 mRNA in v-Src- and mock-NIH3T3 is regulated reciprocally by these factors
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
involved in signal transduction by TRAF2, tumor necrosis factor-alpha receptor-associated factor 2
medicine
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isozyme SPHK1 is a potential therapeutic target in the treatment of inflammatory and autoimmune diseases
medicine
-
targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma
medicine
-
89% of human colon cancer samples tested stain positively for SphK1, whereas normal colon mucosa has negative or weak staining. Adenomas have higher expression of SphK1 versus normal mucosa, and colon cancers with metastasis have higher expression of SphK1 than those without metastasis
medicine
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adenovirus-mediated SPK1 gene transfer promotes recovery of the surgically damaged mesothelial cell layer and prevents postoperative peritoneal adhesion formation
medicine
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after 4 weeks of systemic ovalbumin sensitization and local airway challenge, airway responsiveness increases less in SphK1-/- compared with wild-type mice, whereas pulmonary vascular responsiveness is greatly increased and does not differ between strains. Acute lung inflammation leads to an increase in eosinophils and mRNA expression for sphingosine 1-phosphate phosphatase 2 and sphingosine 1-phosphate lyase in lungs of wild-type but not SphK1-/- mice. After repetitive allergen exposure for 8 weeks, airway responsiveness is not augmented in SphK1-/- or wild-type mice, but pulmonary vascular responsiveness is increased in both strains, with significantly higher vascular responsiveness in SphK1-/- mice compared with that seen in wild-type mice
medicine
-
chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through reactive oxygen species mediated by S1P3 and favourable cardioprotective effects
medicine
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in a mouse model of streptozotocin-induced diabetic nephropathy, isoform Sk1 and connective tisuue grwoth factor CTGF are upregulated in podocytes. In Sk1 deficient mice, exacerbation of diesease is detected by increased albuminuria and CTGF expression when compared to wild-type
medicine
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in a murine collagen-induced arthritis model, prophylactic i.p. administration of SphK1 siRNA significantly reduces the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulates serum levels of sphingosine 1-phosphate, IL-6, TNF-alpha, IFN-gamma, and IgG2a anticollagen Ab. Ex vivo analysis demonstrates significant suppression of collagen-specific proinflammatory/Th1 cytokine IL-6, TNF-alpha, IFN-gamma release in SphK siRNA-treated mice. Mice received with SphK2 siRNA develop more aggressive disease, higher serum levels of IL-6, TNF-alpha, and IFN-gamma, and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients
medicine
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In the azoxymethane murine model of colon cancer, SphK1 and sphingosine 1-phosphate are significantly elevated in colon cancer tissues compared to normal mucosa. Blood levels of sphingosine 1-phosphate are higher in mice with colon cancers than in those without cancers. SphK1-/- mice subjected to azoxymethane have significantly less aberrant crypt foci formation and significantly reduced colon cancer development
medicine
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isoform Sk1 expression is increased in the podocytes of kidney sections of patients with diabetic nephropathy
medicine
isoform SphK1 protein and mRNA levels are higher in clinical tissue samples of patients with non-Hodgkin lymphomas than in reactive lymphoid hyperplasias, with a clear trend towards increasng levels with increasing clinicla grade
medicine
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levels of SPHK1mRNA and protein are higher in gastric cancer cell lines than in normal gastric epithelial cells. SPHK1 protein level is up-regulated in gastric cancer lesions compared with that in the paired adjacent noncancerous tissues. Gastric cancer tissues from 65.7% of patients reveals high level of SPHK1protein expression in contrast to the undetectable or marginally detectable expression of SPHK1 in the adjacent noncancerous gastric tissues. Significantly different expression levels of SPHK1 are found in patients at different clinical stages. Patients with higher SPHK1expression have shorter overall survival time, whereas those with lower SPHK1 expression survive longer
medicine
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patients with breast cancer that express higher CerS2 or 4 mRNA levels tend to show no changes in sphingosine kinase 1 levels, and likewise patients that express no change in CerS2 or CerS4 mRNA levels tend to express higher levels of sphingosine kinase 1. Results suggest an important role for the CerS genes in breast cancer etiology or diagnosis
medicine
-
pharmacologic SphK1 inhibition with B-5354c sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to sphingosine 1-phosphate sphingolipid ratio
medicine
-
sphingosine analogue FTY720, which is activated by phosphorylation specifically by SPHK2, mediates apoptotic signaling of cultured synovial fibroblasts
medicine
-
SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose
medicine
-
SPHK1in astrocytoma cell lines is elevated at both mRNA and protein levels, and the SPHK1 mRNA and protein are significantly up-regulated by up to 6.8- and 40fold, respectively, in primary astrocytomas compared with those in the adjacent noncancerous brain tissues. 41.2% of paraffin-embedded archival astrocytoma biopsies exhibit high expression of SPHK1. The up-regulation of SPHK1 is significantly correlated with the histologic grade of astrocytoma and patients with high SPHK1 level exhibit shorter survival time
medicine
-
synthesis of shingosine kinase substrates as sphingosine 1-phosphate receptor prodrugs, with varying activities at the five sphingosine 1-phosphate receptors
medicine
-
synthesis of shingosine kinase substrates as sphingosine 1-phosphate receptor prodrugs, with varying activities at the five sphingosine 1-phosphate receptors. Substrate (2R)-2-amino-2-[5-(4-octylphenyl)-1H-imidazol-2-yl]propan-1-ol causes lymphopenia for more than 20h
medicine
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the growth of SphK2-deficient MCF-7 breast tumor xenografts is markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors is comparable. Tumor-associated macrophages from SphK2-deficient tumors display a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-alpha, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206
medicine
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the synovial fluid levels of sphingosine 1-phosphate are significantly higher in patients with rheumatoid arthritis than in those with osteoarthritis. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in rheumatoid arthritis
medicine
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treatment of wild-type and Sphk1 null mouse hearts by ischaemic postconditioning. Postconditioning consisting of 5 s of ischaemia and 5 s of reperfusion for three cycles after the index ischaemia, protects hearts against ischaemia/reperfusion injury, recovery of left ventricular developed pressure and maximum velocity of increase or decrease of left ventricular pressure are elevated and left ventricular end-diastolicpressure is decreased, infarction size is reduced from 40% in the control group to 29% of the risk area in the postconditioning group. Phosphorylation of Akt and extracellular signal-regulated kinases is increased at 10 min of reperfusion. The protection induced by postconditioning is abolished in Sphk1 null mouse hearts
medicine
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when sphingosine kinase 1 is deleted in Sandhoff disease mice, a prototypical neuronopathic lysosomal storage disorder, a milder disease course occurs, with decreased proliferation of glial cells and less-pronounced astrogliosis. A similar result of milder disease course and reduced astroglial proliferation is obtained by deletion of the gene for the S1P(3) receptor, a G protein-coupled receptor enriched in astrocytes
medicine
the expression level and properties of N-terminal 86 amino-acid isoform variant of sphingosine kinase 1, SK1b, in prostate cancer cells reduce its sensitivity to proteasomal degradation induced by 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole in comparison to isoform SK1a. The reduced sensitivity of SK1b to proteasomal degradation in response to 2-(4-hydroxyanilino)-4-(4-chlorophenyl)thiazole results in specific changes in ceramide and S1P levels that lead to apoptosis of androgen-sensitive but not androgen-independent LNCaP prostate cancer cells
medicine
sphingosine kinase-1 expression inversely correlates with survival after immune checkpoint inhibitor (ICI) therapy in melanoma tumors. Downregulation of sphingosine kinase-1 improves the efficacy of ICI therapy in various cancer models
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Release 2023.1 (January 2023)
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