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Literature summary for 2.7.1.91 extracted from
- Structure and catalytic function of sphingosine kinases: analysis by site-directed mutagenesis and enzyme kinetics (2013), Biochim. Biophys. Acta, 1831, 139-146.
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene sphK1, sequence comparison of human isozymes sphingosine kinases 1 and 2 | Homo sapiens |
| gene sphK2, sequence comparison of human isozymes sphingosine kinases 1 and 2 | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| D176N | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| D176N/D178N | site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type | Homo sapiens |
| D176N/E180Q | site-directed mutagenesis, the mutant shows 90% reduced activity compared to the wild-type | Homo sapiens |
| D89A | site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane | Homo sapiens |
| E180Q | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| E182Q | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| F197A | site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type | Homo sapiens |
| F197A/L198Q | site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type | Homo sapiens |
| F303H | site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type | Homo sapiens |
| F303H | site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type | Homo sapiens |
| G111A | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G111D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G113A | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| G113D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G212E | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G212E/L218A | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G213E/L219A | site-directed mutagenesis, the mutant is catalytically inactive | Mus musculus |
| G26A | site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type | Homo sapiens |
| G26D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G80A | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G80D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| G82A | site-directed mutagenesis, the mutant shows a 44.7fold increase in Km compared to the wild-type | Homo sapiens |
| G82D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| K103A | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| K103R | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| K27A | site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type | Homo sapiens |
| K29A | site-directed mutagenesis, the mutant shows unaltered kinetics compared to the wild-type | Homo sapiens |
| L134Q | site-directed mutagenesis, the mutant is inactive | Homo sapiens |
| L134Q | site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type | Homo sapiens |
| L147Q | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| L147Q | site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type | Homo sapiens |
| L153Q | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| L153Q | site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type | Homo sapiens |
| L187Q | site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type | Homo sapiens |
| L194Q | site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type | Homo sapiens |
| L198Q | site-directed mutagenesis, the mutant shows 25% reduced activity compared to the wild-type | Homo sapiens |
| L200Q | site-directed mutagenesis, the mutant shows 95% reduced activity compared to the wild-type | Homo sapiens |
| L200Q | site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type | Homo sapiens |
| L218A | site-directed mutagenesis, the mutant shows about 38% of wild-type activity | Homo sapiens |
| L219A | site-directed mutagenesis, the mutant shows about 38% of wild-type activity | Mus musculus |
| additional information | construction of catalytically inactive deletion mutants DELTA1-227 and DELTA227-618 | Mus musculus |
| additional information | construction of catalytically inactive deletion mutants DELTA1226 and DELTA226-619 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| R185A/R186A | site-directed mutagenesis, the mutant shows 75% reduced activity compared to the wild-type | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| S351A | site-directed mutagenesis, the mutant shows about 115% of wild-type activity | Homo sapiens |
| S401A | site-directed mutagenesis, the mutant shows about 109% of wild-type activity | Homo sapiens |
| S430A | site-directed mutagenesis, the mutant shows about 124% of wild-type activity | Homo sapiens |
| S441A | site-directed mutagenesis, the mutant shows about 35% of wild-type activity | Homo sapiens |
| S79A | site-directed mutagenesis, the mutant shows a 1.5fold increase in Km compared to the wild-type | Homo sapiens |
| S79D | site-directed mutagenesis, the mutant is catalytically inactive | Homo sapiens |
| T54A | site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type | Homo sapiens |
| T54A | site-directed mutagenesis, the mutant loses selective binding to vesicles comprised of phosphatidylcholine and phosphatidylserine over those comprised of phosphatidylcholine and phosphatidylglycerol | Homo sapiens |
| T54A | site-directed mutagenesis, the mutant shows 55% reduced activity compared to the wild-type | Homo sapiens |
| T578A | site-directed mutagenesis, the mutant shows about 56% of wild-type activity | Homo sapiens |
| T74A | site-directed mutagenesis, the mutation significantly reduces the preferred binding to plasma over nuclear membrane | Homo sapiens |
| V290N | site-directed mutagenesis, the mutant is inactive | Homo sapiens |
| V290N | site-directed mutagenesis, the mutant shows highly reduced activity compared to the wild-type | Homo sapiens |
| V327A/L328Q | site-directed mutagenesis, the mutant shows about 75% of wild-type activity | Homo sapiens |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| additional information | - |
additional information | kinetic values of wild-type and mutant enzymes, overview | Homo sapiens | |
| 0.00247 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, deletion mutant DELTA364-384 | Homo sapiens |  |
| 0.0102 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant E182Q | Homo sapiens | |
| 0.014 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant K103R | Homo sapiens | |
| 0.018 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant G26A | Homo sapiens | |
| 0.019 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant K29A | Homo sapiens | |
| 0.02 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant G113A | Homo sapiens | |
| 0.02 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant K27A | Homo sapiens | |
| 0.02 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant S79A | Homo sapiens | |
| 0.022 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant G82A | Homo sapiens | |
| 0.0257 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant E180Q | Homo sapiens | |
| 0.0366 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant D176N | Homo sapiens | |
| 0.0628 | - |
ATP | pH and temperature not specified in the publication, mutant E180Q | Homo sapiens | |
| 0.071 | - |
ATP | pH and temperature not specified in the publication, mutant G113A | Homo sapiens | |
| 0.073 | - |
ATP | pH and temperature not specified in the publication, mutant K27A | Homo sapiens | |
| 0.0774 | - |
ATP | pH and temperature not specified in the publication, mutant D176N | Homo sapiens | |
| 0.078 | - |
ATP | pH and temperature not specified in the publication, mutant K29A | Homo sapiens | |
| 0.0884 | - |
ATP | pH and temperature not specified in the publication, mutant D178N | Homo sapiens | |
| 0.09 | - |
ATP | pH and temperature not specified in the publication, mutant G26A | Homo sapiens | |
| 0.092 | - |
ATP | pH and temperature not specified in the publication, mutant K103R | Homo sapiens | |
| 0.0947 | - |
ATP | pH and temperature not specified in the publication, mutant E182Q | Homo sapiens | |
| 0.108 | - |
D-erythro-sphingosine | pH and temperature not specified in the publication, mutant D178N | Homo sapiens | |
| 0.124 | - |
ATP | pH and temperature not specified in the publication, mutant S79A | Homo sapiens | |
| 3.8 | - |
ATP | pH and temperature not specified in the publication, mutant G82A | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| membrane | - |
Homo sapiens | 16020 | - |
| membrane | - |
Mus musculus | 16020 | - |
| 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 | Homo sapiens | - |
- |
| additional information | unlike isozyme SK1, isozyme SK2 does not translocate the membrane fraction following calmodulin binding | Mus musculus | - |
- |
| nucleus | 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 | Homo sapiens | 5634 | - |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 42500 | - |
- |
Homo sapiens |
| 65200 | - |
- |
Homo sapiens |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + D-erythro-sphingosine | Homo sapiens | - |
ADP + D-erythro-sphingosine 1-phosphate | - |
? | |
| ATP + D-erythro-sphingosine | Mus musculus | - |
ADP + D-erythro-sphingosine 1-phosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q9NRA0 | sphingosine kinase isoform 2 | - |
| Homo sapiens | Q9NYA1 | sphingosine kinase isoform 1 | - |
| Mus musculus | Q8CI15 | sphingosine kinase isoform 1 | - |
| Mus musculus | Q9JIA7 | sphingosine kinase isoform 2 | - |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | phosphorylation of S225 results in a 14fold increase in SK1 activity arising from a 13.6fold increase in kcat | Homo sapiens |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + D-erythro-sphingosine | - |
Homo sapiens | ADP + D-erythro-sphingosine 1-phosphate | - |
? | |
| ATP + D-erythro-sphingosine | - |
Mus musculus | ADP + D-erythro-sphingosine 1-phosphate | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 42500 | Homo sapiens |
| ? | x * 65200 | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| SK1 | - |
Homo sapiens |
| SK1 | - |
Mus musculus |
| SK2 | - |
Homo sapiens |
| SK2 | - |
Mus musculus |
| sphingosine kinase 1 | - |
Homo sapiens |
| sphingosine kinase 1 | - |
Mus musculus |
| sphingosine kinase 2 | - |
Homo sapiens |
| sphingosine kinase 2 | - |
Mus musculus |
General Information
| General Information | Comment | Organism |
|---|---|---|
| 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 | Homo sapiens |
| malfunction | single SK1 and SK2 knockout mouse models show little phenotypic change | Mus musculus |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Mus musculus |
| additional information | analysis of the catalytic mechanism of the enzyme | Mus musculus |
| 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 | Homo sapiens |
| additional information | analysis of the catalytic mechanism of the enzyme, sequence comparison of human isozymes sphingosine kinases 1 and 2 | Homo sapiens |
| physiological function | D-erythro-sphingosine 1-phosphate elicits numerous cellular responses via a family of G-protein coupled receptors, as well as intracellular effectors | Mus musculus |
| 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 | Homo sapiens |
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