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Literature summary extracted from

  • Lahiri, S.; Park, H.; Laviad, E.L.; Lu, X.; Bittman, R.; Futerman, A.H.
    Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner (2009), J. Biol. Chem., 284, 16090-16098 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.3.1.24 gene CERS4, recombinant overexpression in HEK cells Homo sapiens
2.3.1.24 gene CERS5, recombinant overexpression in HEK cells, FTY720 inhibits CerS1 activity to a greater extent than CerS5 in the overexpressing cells Homo sapiens
2.3.1.297 gene CERS2, recombinant overexpression in HEK cells Homo sapiens
2.3.1.299 gene CERS1, recombinant overexpression in HEK cells, FTY720 inhibits CerS1 activity to a greater extent than CerS5 in the overexpressing cells Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.1.24 FTY720 inhibits ceramide synthases and upregulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. FTY720 is a sphingosine analogue and in clinical trials as an immunomodulator. Multifaceted mode of interaction between FTY720 and CerS. Conversion to FTY720-phosphate is necessary for its clinical efficacy. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs, dependence on acyl-CoA chain length of inhibition of CerS activity by FTY720. Sphinganine first binds to CerS to form an E-S (CerS-sphinganine) complex, and only after formation of this complex can FTY720 bind. The binding sites of FTY720 and acyl-CoA appear to be distinct, but the interaction between sphinganine binding and FTY720 binding nevertheless impacts the rate of the reaction with respect to acyl-CoA. FTY720 inhibits ceramide synthesis at high sphinganine concentrations in vivo, but not at low concentrations, supporting a complex, possibly allosteric mode of interaction between sphinganine and FTY720 and is consistent with uncompetitive inhibitors being most effective at high substrate concentrations. FTY720 acts as a noncompetitive inhibitor toward C18-CoA. The inhibition of FTY720 toward C18-CoA is allosteric under the normal reaction conditions. Sphingolipid composition of HEK cells treated with FTY720, overview; inhibits ceramide synthases and upregulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. FTY720 is a sphingosine analogue and in clinical trials as an immunomodulator. Multifaceted mode of interaction between FTY720 and CerS. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs. Sphinganine first binds to CerS to form an E-S (CerS-sphinganine) complex, and only after formation of this complex can FTY720 bind. The binding sites of FTY720 and acyl-CoA appear to be distinct, but the interaction between sphinganine binding and FTY720 binding nevertheless impacts the rate of the reaction with respect to acyl-CoA. FTY720 inhibits ceramide synthesis at high sphinganine concentrations in vivo, but not at low concentrations, supporting a complex, possibly allosteric mode of interaction between sphinganine and FTY720 and is consistent with uncompetitive inhibitors being most effective at high substrate concentrations Homo sapiens
2.3.1.24 fumonisin B1
-
 Homo sapiens
2.3.1.24 additional information FTY720-P has no effect on CerS5 activity. In contrast to the dual effects of fumonisin B1, which is only observed in cells overexpressing CerS, FTY720 elevates ceramide levels in untransfected cells. Dimethylsphingosine has no effect on CerS5 activity; in contrast to the dual effects of fumonisin B1, which is only observed in cells overexpressing CerS, FTY720 elevates ceramide levels in untransfected cells. Dimethylsphingosine has no effect on CerS4 activity Homo sapiens
2.3.1.297 FTY720 inhibits ceramide synthases and upregulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. FTY720 is a sphingosine analogue and in clinical trials as an immunomodulator. Multifaceted mode of interaction between FTY720 and CerS. FTY720 itself and not FTY720-P, is responsible for CerS2 inhibition. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs. Sphinganine first binds to CerS to form an E-S (CerS-sphinganine) complex, and only after formation of this complex can FTY720 bind. The binding sites of FTY720 and acyl-CoA appear to be distinct, but the interaction between sphinganine binding and FTY720 binding nevertheless impacts the rate of the reaction with respect to acyl-CoA. FTY720 inhibits ceramide synthesis at high sphinganine concentrations in vivo, but not at low concentrations, supporting a complex, possibly allosteric mode of interaction between sphinganine and FTY720 and is consistent with uncompetitive inhibitors being most effective at high substrate concentrations. Inhibition of CerS2 by FTY720 does not occur via a nonspecific mechanism Homo sapiens
2.3.1.297 fumonisin B1
-
 Homo sapiens
2.3.1.297 additional information in contrast to the dual effects of fumonisin B1, which is only observed in cells overexpressing CerS, FTY720 elevates ceramide levels in untransfected cells. Lysophosphatidic acid does not inhibit CerS2. Dimethylsphingosine has no effect on CerS2 activity Homo sapiens
2.3.1.297 sphingosine 1-phosphate significantly inhibits CerS2, CerS2 contains a sphingosine 1-phosphate receptor-like motif via which sphingosine 1-phosphate inhibits CerS2 activity Homo sapiens
2.3.1.299 FTY720 inhibits ceramide synthases and upregulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. FTY720 is a sphingosine analogue and in clinical trials as an immunomodulator. Multifaceted mode of interaction between FTY720 and CerS. FTY720 inhibits ceramide synthesis using C18-CoA to a greater extent than other acyl-CoAs, dependence on acyl-CoA chain length of inhibition of CerS activity by FTY720. Sphinganine first binds to CerS to form an E-S (CerS-sphinganine) complex, and only after formation of this complex can FTY720 bind. The binding sites of FTY720 and acyl-CoA appear to be distinct, but the interaction between sphinganine binding and FTY720 binding nevertheless impacts the rate of the reaction with respect to acyl-CoA. FTY720 inhibits ceramide synthesis at high sphinganine concentrations in vivo, but not at low concentrations, supporting a complex, possibly allosteric mode of interaction between sphinganine and FTY720 and is consistent with uncompetitive inhibitors being most effective at high substrate concentrations. FTY720 acts as a noncompetitive inhibitor toward C18-CoA. The inhibition of FTY720 toward C18-CoA is allosteric under the normal reaction conditions. Sphingolipid composition of HEK cells treated with FTY720, overview Homo sapiens
2.3.1.299 fumonisin B1
-
 Homo sapiens
2.3.1.299 additional information in contrast to the dual effects of fumonisin B1, which is only observed in cells overexpressing CerS, FTY720 elevates ceramide levels in untransfected cells Homo sapiens

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.3.1.24 Mg2+ activates Homo sapiens
2.3.1.297 Mg2+ activates Homo sapiens
2.3.1.299 Mg2+ activates Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.24 sphinganine + arachidoyl-CoA Homo sapiens
-
 N-arachidoylsphinganine + CoA
-
 ?
2.3.1.24 sphinganine + palmitoyl-CoA Homo sapiens
-
 N-palmitoylsphinganine + CoA
-
 ?
2.3.1.24 sphinganine + stearoyl-CoA Homo sapiens
-
 N-stearoylsphinganine + CoA
-
 ?
2.3.1.297 sphinganine + behenoyl-CoA Homo sapiens
-
 N-behenoylsphinganine + CoA
-
 ?
2.3.1.297 sphinganine + lignoceroyl-CoA Homo sapiens
-
 N-lignoceroylsphinganine + CoA
-
 ?
2.3.1.299 sphinganine + stearoyl-CoA Homo sapiens
-
 N-stearoylsphinganine + CoA
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.1.24 Homo sapiens Q8N5B7
-
-
2.3.1.24 Homo sapiens Q9HA82
-
-
2.3.1.297 Homo sapiens Q96G23
-
-
2.3.1.299 Homo sapiens P27544
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.3.1.24 erythrocyte
-
 Homo sapiens
-
2.3.1.24 HEK-293T cell
-
 Homo sapiens
-
2.3.1.24 Hep-G2 cell
-
 Homo sapiens
-
2.3.1.24 lung
-
 Homo sapiens
-
2.3.1.297 erythrocyte
-
 Homo sapiens
-
2.3.1.297 HEK-293T cell
-
 Homo sapiens
-
2.3.1.297 lung
-
 Homo sapiens
-
2.3.1.299 erythrocyte
-
 Homo sapiens
-
2.3.1.299 HEK-293T cell
-
 Homo sapiens
-
2.3.1.299 lung
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.24 sphinganine + arachidoyl-CoA
-
 Homo sapiens N-arachidoylsphinganine + CoA
-
 ?
2.3.1.24 sphinganine + palmitoyl-CoA
-
 Homo sapiens N-palmitoylsphinganine + CoA
-
 ?
2.3.1.24 sphinganine + stearoyl-CoA
-
 Homo sapiens N-stearoylsphinganine + CoA
-
 ?
2.3.1.297 sphinganine + behenoyl-CoA
-
 Homo sapiens N-behenoylsphinganine + CoA
-
 ?
2.3.1.297 sphinganine + lignoceroyl-CoA
-
 Homo sapiens N-lignoceroylsphinganine + CoA
-
 ?
2.3.1.299 sphinganine + stearoyl-CoA
-
 Homo sapiens N-stearoylsphinganine + CoA
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.3.1.24 ceramide synthase 4
-
 Homo sapiens
2.3.1.24 ceramide synthase 5
-
 Homo sapiens
2.3.1.24 CerS4
-
 Homo sapiens
2.3.1.24 CerS45
-
 Homo sapiens
2.3.1.297 ceramide synthase 2
-
 Homo sapiens
2.3.1.297 CerS2
-
 Homo sapiens
2.3.1.299 ceramide synthase 1
-
 Homo sapiens
2.3.1.299 CerS1
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.3.1.24 37
-
 assay at Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.3.1.24 7.4
-
 assay at Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
2.3.1.24 additional information
-
 additional information kinetic analysis of CerS4 inhibition by FTY 720, FTY720 inhibits CerS4 via noncompetitive inhibition toward C18-acyl-CoA Homo sapiens

General Information

EC Number General Information Comment Organism
2.3.1.24 malfunction upon incubation of HEK cells with inhibitor FTY720, an increase in ceramide levels is observed, with no change in endogenous sphinganine levels. Similar increases are observed for hexosylceramide and sphingomyelin. Moreover, levels of C18-C22-ceramide are significantly increased, as were levels of C18-C22-hexosylceramide and C18-C22-sphingomyelin. This result is consistent with a complex mode of interaction of FTY720 with CerS, perhaps involving an allosteric element that is not preserved in vitro, whereby ceramide synthesis is stimulated in cells despite its inhibition by FTY720 in vitro Homo sapiens
2.3.1.299 malfunction upon incubation of HEK cells with inhibitor FTY720, an increase in ceramide levels is observed, with no change in endogenous sphinganine levels. Similar increases are observed for hexosylceramide and sphingomyelin. Moreover, levels of C18-C22-ceramide are significantly increased, as are levels of C18-C22-hexosylceramide and C18-C22-sphingomyelin. This result is consistent with a complex mode of interaction of FTY720 with CerS, perhaps involving an allosteric element that is not preserved in vitro, whereby ceramide synthesis is stimulated in cells despite its inhibition by FTY720 in vitro Homo sapiens