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Information on EC 1.14.19.17 - sphingolipid 4-desaturase and Organism(s) Homo sapiens
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1.14.19.17 sphingolipid 4-desaturaseIUBMB Comments
The enzyme, which has been characterized from plants, fungi, and mammals, generates a trans double bond at position 4 of sphinganine bases in sphingolipids . The preferred substrate is dihydroceramide, but the enzyme is also active with dihydroglucosylceramide . Unlike EC 1.14.19.29, sphingolipid 8-desaturase, this enzyme does not contain an integral cytochrome b5 domain and requires an external cytochrome b5 . The product serves as an important signalling molecules in mammals and is required for spermatide differentiation .
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dhcers
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- drug development
- pharmacology
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
degs1, dihydroceramide desaturase, des-1, degs2, dihydroceramide desaturase 1, dihydroceramide delta4-desaturase, sphingolipid delta4-desaturase, dihydroceramide desaturase-1, delta4 desaturase, membrane lipid desaturase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dehydroceramide desaturase
-
-
-
-
DES1
dihydroceramide desaturase
dihydroceramide desaturase 1
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+ = a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
the desaturation reaction catalyzed by Des1 is presumably initiated by an enzyme-bound iron-oxo species that abstracts specifically the C-4 pro (R)-hydrogen atom from the substrate. FAD takes electrons from NADH and delivers them to ferrocytochrome b5 with bound Fe3+, which is converted to ferricytochrome b5 with Fe2+. Cytochrome b5-Fe2+ passes the electrons to another enzyme-bound Fe3+ to reduce O2 and form ceramide from dihydroceramide
SYSTEMATIC NAME
IUBMB Comments
dihydroceramide,ferrocytochrome b5:oxygen oxidoreductase (4,5-dehydrogenating)
The enzyme, which has been characterized from plants, fungi, and mammals, generates a trans double bond at position 4 of sphinganine bases in sphingolipids [1]. The preferred substrate is dihydroceramide, but the enzyme is also active with dihydroglucosylceramide [2]. Unlike EC 1.14.19.29, sphingolipid 8-desaturase, this enzyme does not contain an integral cytochrome b5 domain [4] and requires an external cytochrome b5 [3]. The product serves as an important signalling molecules in mammals and is required for spermatide differentiation [5].
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
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
dihydroceramide + ferrocytochrome b5 + O2 + H+
(4E)-sphing-4-enine ceramide + ferricytochrome b5 + H2O
-
-
-
?
N-((2S,3R,6E)-1,3-dihydroxyoctadec-6-en-2-yl)-6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanamide + 2 ferrocytochrome b5 + O2 + 2 H+
N-((2S,3R,4E,6E)-1,3-dihydroxyoctadeca-4,6-dien-2-yl)-6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanamide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
N-((2S,3R,6E)-1,3-dihydroxyoctadec-6-en-2-yl)octanamide + 2 ferrocytochrome b5 + O2 + 2 H+
N-((2S,3R,4E,6E)-1,3-dihydroxyoctadeca-4,6-dien-2-yl)octanamide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
N-((2S,3R,6Z)-1,3-dihydroxyoctadec-6-en-2-yl)-6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanamide + 2 ferrocytochrome b5 + O2 + 2 H+
N-((2S,3R,4E,6Z)-1,3-dihydroxyoctadeca-4,6-dien-2-yl)-6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanamide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
N-((2S,3R,6Z)-1,3-dihydroxyoctadec-6-en-2-yl)octanamide + 2 ferrocytochrome b5 + O2 + 2 H+
N-((2S,3R,4E,6Z)-1,3-dihydroxyoctadeca-4,6-dien-2-yl)octanamide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
N-octanoylsphinganine + ferrocytochrome b5 + O2 + 2 H+
N-octanoylsphingosine + ferricytochrome b5 + 2 H2O
-
-
-
-
?
N-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphinganine + 2 ferrocytochrome b5 + O2 + 2 H+
?
N-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphinganine + reduced acceptor + O2 + 2 H+
?
-
-
-
-
?
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
-
-
?
N-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphinganine + 2 ferrocytochrome b5 + O2 + 2 H+
?
-
-
-
-
?
N-[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphinganine + 2 ferrocytochrome b5 + O2 + 2 H+
?
-
fluorescence-lebeld substrate
-
-
?
additional information
?
-
-
configurational preference of dihydroceramide desaturase-1 towards DELTA6-unsaturated substrates. Establishment of an assay for Des1 activity based on the use of an immobilized DELTA6-monoene as a substrate for further click reaction of the resulting diene with a labelable dienophile, chemical synthesis of DELTA6 and DELTA4,6 sphingoid bases, substrate specificity, overview
-
-
?
additional information
?
-
the electron provided by NAD(P)H is sequentially transported from the cofactor to NADH-cytochrome b5 reductase, cytochrome b5, and the terminal desaturase, which reduces oxygen to water and oxidizes dihydroceramide to ceramide. Desaturation of the D-erythro-isomer by Des1 is much faster than that of the L or D-threo-isomers
-
-
?
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
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
dihydroceramide + ferrocytochrome b5 + O2 + H+
(4E)-sphing-4-enine ceramide + ferricytochrome b5 + H2O
-
-
-
?
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
-
-
-
?
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD(P)H
Des1 requires NADPH or NADH as electron donor and oxygen as electron acceptor
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
required for the catalytic reaction, oscillates from Fe2+ to Fe3+, bound to the enzyme and to cofactor cytochrome b5
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(Z)-4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-N-hydroxybenzimidamide
-
completely inhibits Des1 activity at 0.01 mM but shows little activity at 0.001 mM
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
-
i.e. ABC294640
4-((4-(4-chlorophenyl)thiazol-2-yl)amino)phenol
-
i.e. SKI-II, noncompetitive inhibitor of enzyme Des1, structure-activity relationship analysis, inhibition mechanism, overview
4-[[4-(4-chlorophenyl)-2-thiazolyl]amino]phenol
i.e. dual sphingosine kinase 1-2 inhibitor SKI II, a noncompetitive inhibitor of Des1 activity, molecular modeling studies
gamma-tocopherol
i.e. (2 R)-2,7,8-trimethyl-2-[(4 R,8 R)-4,8,12-trimethyltridecyl]-6-chromanol, a natural component of vitamin E
N-((2S,3R,6E)-1,3-dihydroxyoctadec-6-en-2-yl)octanamide
-
substrate inhibition, non-competitive type of inhibition
SKI II
-
noncompetitive inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II, a dual inhibitor of sphingosine kinases (SKs) 1 and 2, overview. Use of SKI II in the context of cancer therapy
celecoxib
i.e. 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide. Celecoxib induces apoptosis and autophagy in gastric cancer cells through the phosphatidylinositol 3-kinase B signaling pathway
curcumin
i.e. (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione. Curcumin caused a 28% inhibition of Des 1 activity in human gastric adenocarcinoma HGC27 cell lysates at 0.01 mM. Physiological effects, detailed overview
DELTA9-tetrahydrocannabinol
i.e. (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6 H-benzo[c]chromen-1-ol or THC, physiological effects, detailed overview
fenretinide
i.e. N-(4-hydroxyphenyl) retinamide, fenretinide directly targets and irreversibly inhibits DEGS1 in a time-dependent manner, by disrupting the electron transport necessary for desaturation
fenretinide
i.e. N-(4-hydroxyphenyl) retinamide or 4-HPR, a synthetic derivate of all-trans-retinoic acid, 4-HPR inhibition of Des1 might occur indirectly through increased oxidative species in vivo, but Des1 is a direct in vitro target for 4-HPR, which provokes an irreversible inhibition upon long incubation times. Inhibition mechanism, overview
fenretinide
-
a direct inhibitor of Des1 that initially shows competitive inhibition but becomes an irreversible inhibitor over longer incubation times. The 4-aminophenol may play an important role in mediating its irreversible inhibition of Des1, where Des1 oxidation of this group generates a reactive iminoquinone intermediate that reacts with nucleophilic sites on the protein, leading to time-dependent irreversible inhibition of Des1, inhibition mechanism, overview
fenretinide
-
the Des1 inhibitor induces a reduction in SK1a expression and an increase in p53 and p21 expression
fenretinide
i.e. N-(4-hydroxyphenyl)retinamide, a synthetic retinoid, leads to an increase in C16 and C18 dihydroceramide substrate accumulation
gamma-tocotrienol
i.e. (R)-gamma-tocotrienol or [R-(E,E)]-3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2 H-1-benzopyran-6-ol, a natural component of vitamin E
gamma-tocotrienol
a component of vitamin E, gammaTE, inhibits DEGS and decreases de novo ceramide synthesis, elevation of ceramides during prolonged gammaTE treatment is likely caused by sphingomeylinase-mediated hydrolysis of sphingomyelin
GT11
a cyclopropenylceramide (C8CCP) that acts in primary neuronal cultures as a potent specific and competitive inhibitor of DESG1 at concentrations up to 0.001 mM
GT11
i.e. C8-cyclopropenylceramide, competitive inhibition, is active both in vitro and in intact cells
XM462
a 5-thiadihydroceramide, enzyme mechanism-based inhibitor. XM462 has been used as a pharmacological tool to show the role of dhCer as inducer of autophagy in human gastric cancer cell line HGC27
additional information
-
in T98G and U87MG glioblastoma cell lines different Des1 inhibitory pro-autophagic compounds (DIPACS) exhibiting different cytotoxicities (CCX, PXD, resveratrol, gamma-tocotrienol and XM462), trigger autophagy via different pathways, both dihydroceramide-dependent and independent pathways
-
additional information
-
no inhibition by (2S,3S)-2-((4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)benzyl)-carbamoyl)-3-hydroxypyrrolidin-1-ium, 4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)phenol, (Z)-4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-N?-hydroxybenzimidamide, amino(4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-phenyl)methaniminium, (E)-4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)amino)-benzaldehyde oxime, and 5-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-amine
-
additional information
no inhibition of the enzyme by N-[4-methoxyphenyl]retinamide and by non-retinoid RBP4 ligand A1120, RBP4 is a serum retinol-binding protein. The presence of fenretinide or 4-oxo-N-(4-hydroxyphenyl)retinamide leads to 2.7 and 3fold increases in ratio for C16 and C18 ceramides ratio respectively
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0003
4-[[4-(4-chlorophenyl)-2-thiazolyl]amino]phenol
pH and temperature not specified in the publication
0.0001114
N-((2S,3R,6E)-1,3-dihydroxyoctadec-6-en-2-yl)octanamide
-
pH 7.4, 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
within the neural retina, Des1 is expressed in Müller cells, the site of the proposed alternative visual cycle. Des1 is also expressed in the retinal pigment epithelium, where it may augment synthesis of cis-11-retinol
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
-
DES1 inhibition by specific siRNA causing DES1 activity decrease can ameliorate the increase in ceramide, enhance dihydroceramide elevation, and inhibit the palmitic acid-induced increases in caspase 9 activity and caspase 3 activity, palmitic acid-mediated apoptosis and cell growth inhibition are also attenuated by DES1 downregulation
malfunction
-
Des1 inhibition is primarily responsible for the antiproliferative effects of SKI-II and its analogues. The structure-activity relationship of Des1 inhibition correlates to that required for inhibition of PC-3 cell growth, indicating that Des1 inhibition is a key driver of the anticancer effects of SKI-II and it analogues, which is also supported by lipidomic studies in PC-3 cells
malfunction
DESG1 inhibition block the cell growth, cell migration, cytoskeleton modification, response to insulin, impair of endomembrane trafficking. Fenretinide can exert part of its insulin sensitising effects in liver and muscle by inhibiting DEGS1 and hence decreasing the synthesis of ceramides with the concomitant increase in diydroceramide levels
malfunction
-
dihydroceramide desaturase 1 inhibitors activate autophagy via both dihydroceramide-dependent and independent pathways and the balance between the two pathways influences the final cell fate. Enzyme inhibitors celecoxib, resveratrol, phenoxodiol, and gamma-tocotrienol, but not gamma-tocopherol at 0.05 mM, promote an increase in dihydroceramide, dihydrosphingomyelins, and lactosyldihydroceramides in U-87MG and T-98G cell lines. Similar results are found with the active site-directed Des1 inhibitor XM462
malfunction
gamma-tocotrienol inhibits cellular dihydroceramide desaturase (DEGS) activity without affecting its protein expression or de novo synthesis of sphingolipids. Unlike the effect on dihydroceramides, gamma-tocotrienol decreases ceramides (Cers) after 8-h treatment but increases C18:0-Cer and C16:0-Cer after 16 and 24 h, respectively. The increase of ceramides coincides with gamma-tocotrienol-induced apoptosis and autophagy. Since gamma-tocotrienol inhibits DEGS and decreases de novo ceramide synthesis, elevation of ceramides during prolonged gamma-tocotrienol treatment is likely caused by sphingomeylinase-mediated hydrolysis of sphingomyelin. gamma-Tocotrienol treatment led to a time- and dose-dependent decrease in viability of colon, pancreatic and breast cancer cells, overview
malfunction
-
inhibitors SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 in LNCaP-AI prostate cancer cells. Inhibitors SKi, ABC294640, or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 fails to increase p53 and p21 expression, but the former reduces DNA synthesis in LNCaP-AI prostate cancer cells. N-acetylcysteine (reactive oxygen species scavenger) blocks the SK inhibitor-induced increase in p21 and p53 expression but has no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increases p53 expression while a combination of Des1/SK1 siRNA increases the expression of p21. Modulation of both de novo and sphingolipid rheostat pathways in order to induce growth arrest can be achived by targeting androgen-independent prostate cancer cells with compounds that affect the enzymes Des1 and SK1. N-acetyl cysteine has no effect on the ABC294640-induced proteasomal degradation of Des1, suggesting that the oxidative stress response is down stream of Des1
metabolism
-
enzymes Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways
metabolism
-
in the de novo synthesis, ceramide synthases catalyze the N-acylation of sphinganine to dihydroceramide, which is finally converted to ceramide by introduction of an (E)-4 double bond. The last step is catalyzed by dihydroceramide desaturase 1 (Des1), the enzyme that regulates the balance between dihydroceramide and ceramide
metabolism
the enzyme catalyses the final step in the de novo biosynthesis of ceramides controlling the step from dihydroceramides to ceramides
metabolism
the enzyme catalyzes the oxidation of dhCer to ceramide (Cer) by dihydroceramide desaturase 1 (Des1), the last step of the de novo sphingolipids biosynthetic pathway. Ceramides, and, to a lesser extent, dihydroceramides are further metabolized to complex sphingolipids, such as (dihydro) sphingomyelins and (dihydro) glycosphingolipids by other enzymes
physiological function
DELTA4-desaturated sphingolipids provide an early signal necessary to trigger the entry into both meiotic and spermatid differentiation pathways during spermatogenesis
physiological function
dihydroceramide desaturase (Des1) is the last enzyme in the de novo synthesis of ceramides (Cer). It catalyzes the insertion of a double bond into dihydroceramides (dhCer) to convert them to Cer, both of which are further metabolized to more complex (dihydro) sphingolipids. Dihydroceramides are implicated in a wide spectrum of biological processes. Des1 is regulated by fatty acids, myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane, where it causes an increase in ceramide levels that in turn leads to apoptosis. Des1 is upregulated under hypoxia to cope with the decreased enzyme activity and the consequent raise in dhCer production. Des1 is also expressed in the retinal pigment epithelium, where it may augment synthesis of cis-11-retinol. By producing (cis)-9-retinol, which can be readily converted to (cis)-9-retinoic acid, Des1 is the only known source of 9-cis-retinoids in vertebrates. Des1, by means of its isomerase-2 activity, may play a role in nonvisual processes such as cell growth, differentiation, apoptosis and malignant transformation by contributing to the synthesis of (cis)-9-retinoic acid. Addition of all-trans-retinol to Des 1-expressing 293T cell homogenates or to purified Des1 expressed in Escherichia coli results in the formation of (cis)-11-retinol, (cis,cis)-9,13-retinol, (cis)-9-retinol and (cis)-13-retinol at ratios similar to those seen after iodine-catalyzed retinoid equilibration. The rate of Des1-catalyzed retinol equilibration is very high
physiological function
-
dihydroceramide desaturase (Des1), the last enzyme in the de novo synthesis of ceramide (Cer), regulates the balance between dihydroceramides (dhCers) and ceramides
physiological function
-
dihydroceramide desaturase 1 (Des1) catalyzes the last step of ceramide synthesis de novo, thus regulating the physiologically relevant balance between dihydrosphingolipids and sphingolipids
physiological function
-
dihydroceramide-desaturase-1-mediated caspase 9 activation through ceramide plays a pivotal role in palmitic acid-induced HepG2 cell apoptosis. Enzyme dihydroceramide desaturase 1 (DES1) plays a key role in palmitic acid-mediated caspase 9 and caspase 3 activation. Palmitoleic acid, an omega-7 monounsaturated fatty acid, reverses palmitic acid-induced apoptosis through DES1 - ceramide - caspase 9 - caspase 3 signaling
physiological function
enzyme dihydroceramide desaturase 1 is the gatekeeper of ceramide induced lipotoxicity. The enzyme is dysregulated by factors such as oxidative stress, hypoxia and inflammation. Dihydroceramides constitute a biologically active molecule from the sphingolipid family with certain differential characteristics with respect to its delta-4 unsaturated counterparts, the ceramides. DESG1 acts as a vitamin A isomerase in Muller glial cells of the retina. DEGS1 acts as oxygen biosensor. It is involved in the inflammation signalling initiated by interferon gamma and in the inflammation signalling mediated by interleukin-2, IL-2. DEGS1 may play a role in controlling and participating in the levels of ceramides normally associated to inflammation processes. Biological role of dihydroceramides, e.g. in apoptosis and autophagy, in the cell cycle, or as regulators of lipid homeostasis, detailed overview. Dihydroceramides correlate better than ceramides with body mass index (BMI) and waist circumference in cohorts of overweight-obese subjects
physiological function
-
the de novo synthesis of sphingolipids commences with palmitoyl CoA, which is converted into the central lipid ceramide (Cer) in four steps, the last step being the introduction of the double bond at C4 by dihydroceramide desaturase-1 (Des1)
additional information
-
computational ligand docking study and simulations using enzyme structures PDB IDs BC5R and 1IB0, overview
additional information
lipid and ceramide content analysis in untreated and inhibitor-treated ARPE-19 cells, overview
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). DEGS1_HUMAN
323
6
37866
Swiss-Prot
other Location (Reliability: 3)
DEGS2_HUMAN
323
1
37197
Swiss-Prot
other Location (Reliability: 4)
A0A024R3P1_HUMAN
323
6
37866
TrEMBL
other Location (Reliability: 3)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane, where it causes an increase in ceramide levels that in turn leads to apoptosis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
L175Q
naturally occuring mutation, the mutation is is associated with increased levels of dihydroceramides, decreased levels of cholesterol esters and decreased waist to hip ratio
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene degs-1, recombinant expression in Escherichia coli and in 293-T cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
Des1 is upregulated under hypoxia. Upregulation of Des1 occurs by saturated fatty acids and anoxia
gamma-tocotrienol causes downregulation of Des1 expression but is not inhibitory for the enzyme activity
-
interferon gamma upregulates expression levels of DEGS1 in the human mononuclear cell line THP-1, similarly, interleukin 2 increases expression levels of DEGS1 in human natural killer cells. all trans-Retinoic acid increases the enzyme expression
natural forms of vitamin E can induce dihydroceramide levels by repressing DEGS1 activity. Adiponectin represses the expression of degs1 in MCF-7 cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
pharmacology
-
the cells capacity to biosynthesize dihydroceramides must be taken into account in proautophagic Des1 inhibitors-including therapies
drug development
Des1 is a potential therapeutic target for combating HIV-1 infection
drug development
enzyme DES1 inhibition is used in treatment of cancer, it is a target for fenretinide and fenretinide metabolites
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ternes, P.; Franke, S.; Zaehringer, U.; Sperling, P.; Heinz, E.
Identification and characterization of a sphingolipid delta 4-desaturase family
J. Biol. Chem.
277
25512-25518
2002
Caenorhabditis elegans (G5EC63), Mus musculus (O09005), Mus musculus, Homo sapiens (O15121), Homo sapiens, Candida albicans (Q5AJX2), Candida albicans, Drosophila melanogaster (Q94515), Drosophila melanogaster
Zhu, Q.; Yang, J.; Zhu, R.; Jiang, X.; Li, W.; He, S.; Jin, J.
Dihydroceramide-desaturase-1-mediated caspase 9 activation through ceramide plays a pivotal role in palmitic acid-induced HepG2 cell apoptosis
Apoptosis
21
1033-1044
2016
Homo sapiens
Rodriguez-Cuenca, S.; Barbarroja, N.; Vidal-Puig, A.
Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity
Biochim. Biophys. Acta
1851
40-50
2015
Chlorocebus aethiops, Mus musculus (O09005), Homo sapiens (O15121), Drosophila melanogaster (Q94515)
Casasampere, M.; Ordonez, Y.F.; Casas, J.; Fabrias, G.
Dihydroceramide desaturase inhibitors induce autophagy via dihydroceramide-dependent and independent mechanisms
Biochim. Biophys. Acta
1861
264-275
2017
Homo sapiens
Pou, A.; Abad, J.L.; Ordonez, Y.F.; Garrido, M.; Casas, J.; Fabrias, G.; Delgado, A.
From the configurational preference of dihydroceramide desaturase-1 towards DELTA6-unsaturated substrates to the discovery of a new inhibitor
Chem. Commun. (Camb.)
53
4394-4397
2017
Homo sapiens
Casasampere, M.; Ordonez, Y.F.; Pou, A.; Casas, J.
Inhibitors of dihydroceramide desaturase 1 Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology
Chem. Phys. Lipids
197
33-44
2016
Drosophila melanogaster, Drosophila melanogaster (Q94515), Mus musculus (O09005), Homo sapiens (O15121), Rattus norvegicus (Q5XIF5)
Cingolani, F.; Casasampere, M.; Sanllehi, P.; Casas, J.; Bujons, J.; Fabrias, G.
Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II
J. Lipid Res.
55
1711-1720
2014
Homo sapiens
Aurelio, L.; Scullino, C.V.; Pitman, M.R.; Sexton, A.; Oliver, V.; Davies, L.; Rebello, R.J.; Furic, L.; Creek, D.J.; Pitson, S.M.; Flynn, B.L.
From sphingosine kinase to dihydroceramide desaturase a structure-activity relationship (SAR) study of the enzyme inhibitory and anticancer activity of 4-((4-(4-chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II)
J. Med. Chem.
59
965-984
2016
Homo sapiens
Jang, Y.; Rao, X.; Jiang, Q.
Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment
J. Nutr. Biochem.
46
49-56
2017
Homo sapiens (O15121)
McNaughton, M.; Pitman, M.; Pitson, S.M.; Pyne, N.J.; Pyne, S.
Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells
Oncotarget
7
16663-16675
2016
Homo sapiens
Poliakov, E.; Samuel, W.; Duncan, T.; Gutierrez, D.B.; Mata, N.L.; Redmond, T.M.
Inhibitory effects of fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on fenretinide molecular targets beta-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide DELTA4-desaturase 1
PLoS ONE
12
e0176487
2017
Mus musculus (O09005), Homo sapiens (O15121), Mus musculus C57BL/6 (O09005)
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