Literature summary for 2.3.1.24 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 .

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Cloned(Commentary)

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

Inhibitors

Inhibitors	Comment	Organism	Structure
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
fumonisin B1	-	Homo sapiens
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

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	activates	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
sphinganine + arachidoyl-CoA	Homo sapiens	-	N-arachidoylsphinganine + CoA	-	?
sphinganine + palmitoyl-CoA	Homo sapiens	-	N-palmitoylsphinganine + CoA	-	?
sphinganine + stearoyl-CoA	Homo sapiens	-	N-stearoylsphinganine + CoA	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q8N5B7	-	-
Homo sapiens	Q9HA82	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
erythrocyte	-	Homo sapiens	-
HEK-293T cell	-	Homo sapiens	-
Hep-G2 cell	-	Homo sapiens	-
lung	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
sphinganine + arachidoyl-CoA	-	Homo sapiens	N-arachidoylsphinganine + CoA	-	?
sphinganine + palmitoyl-CoA	-	Homo sapiens	N-palmitoylsphinganine + CoA	-	?
sphinganine + stearoyl-CoA	-	Homo sapiens	N-stearoylsphinganine + CoA	-	?

Synonyms

Synonyms	Comment	Organism
ceramide synthase 4	-	Homo sapiens
ceramide synthase 5	-	Homo sapiens
CerS4	-	Homo sapiens
CerS45	-	Homo sapiens

Temperature Optimum [°C]

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

pH Optimum

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

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
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

General Information	Comment	Organism
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

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Release 2023.1 (January 2023)