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sphingosine-1-phosphate lyase 1

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2522

Nomenclature: sphingosine-1-phosphate lyase 1

Family: Sphingosine 1-phosphate lyase

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 568 10q22.1 SGPL1 sphingosine-1-phosphate lyase 1
Mouse 1 568 10 32.14 cM Sgpl1 sphingosine phosphate lyase 1
Rat 1 568 20q11 Sgpl1 sphingosine-1-phosphate lyase 1
Previous and Unofficial Names Click here for help
S1PL | Sphingosine-1-phosphate aldolase | SPL 1 | SP-lyase 1 | sphinganine-1-phosphate aldolase
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 4.1.2.27 Sphingosine 1-phosphate -> phosphoethanolamine + hexadecenal
dihydrosphingosine 1-phosphate -> phosphoethanolamine + hexadecanal
Cofactors Click here for help
Cofactor Species Comments Reference
pyridoxal 5-phosphate None

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 31 [PMID: 24809814] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.7 pIC50 5-8
pIC50 6.7 (IC50 2.1x10-7 M) [5-8]
LX2931 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition <4.0 pIC50 8
pIC50 <4.0 (IC50 >1x10-4 M) [8]
Immunopharmacology Comments
Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. S1PL knockout mice with partial reduction of S1PL activity exhibit profoundly reduced T cell immigration [3], an effect that is mediated by elevated S1P levels. Elevated S1P acts to functionally antagonise the S1PR signalling pathway (via receptor internalisation and desensitisation), which results in inhibition of lymphocyte egress from secondary immune tissues and causes peripheral lymphopenia and immunosuppression. S1PL-deficient mice also exhibit resistance to various inflammatory and autoimmune challenges. Pharmacological S1PL inhibitors recapitulate the effect of gene-knockdown. These findings suggest that inhibition of S1PL represents a novel therapeutic strategy for the treatment of autoimmune disorders. As a result, S1PL inhibitors are being investigated for their potential to treat T cell dependent autoimmune diseases [2,4,8].
Immuno Process Associations
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0030097 hemopoiesis IEA
Clinically-Relevant Mutations and Pathophysiology Comments
A homozygous point mutation results in mislocalisation of S1P lyase from the endoplasmic reticulum in pediatric alveolar rhabdomyosarcoma [1].
General Comments
S1PL is a microsomal enzyme that tightly regulates intracellular S1P levels. It catalyzes the irreversible retro-aldol reaction of S1P to 2-hexadecenal and phosphoethanolamine.

References

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1. Adamus A, Engel N, Seitz G. (2020) SGPL1321 mutation: one main trigger for invasiveness of pediatric alveolar rhabdomyosarcoma. Cancer Gene Ther, 27 (7-8): 571-584. [PMID:31455837]

2. Bagdanoff JT, Donoviel MS, Nouraldeen A, Carlsen M, Jessop TC, Tarver J, Aleem S, Dong L, Zhang H, Boteju L et al.. (2010) Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). J Med Chem, 53 (24): 8650-62. [PMID:21090716]

3. Billich A, Baumruker T, Beerli C, Bigaud M, Bruns C, Calzascia T, Isken A, Kinzel B, Loetscher E, Metzler B et al.. (2013) Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis. PLoS ONE, 8 (3): e59630. [PMID:23544080]

4. Fleischmann R. (2012) Novel small-molecular therapeutics for rheumatoid arthritis. Curr Opin Rheumatol, 24 (3): 335-41. [PMID:22357358]

5. Harris CM, Mittelstadt S, Banfor P, Bousquet P, Duignan DB, Gintant G, Hart M, Kim Y, Segreti J. (2016) Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats. J Pharmacol Exp Ther, 359 (1): 151-8. [PMID:27519818]

6. Loetscher E, Schneider K, Beerli C, Billich A. (2013) Assay to measure the secretion of sphingosine-1-phosphate from cells induced by S1P lyase inhibitors. Biochem Biophys Res Commun, 433 (3): 345-8. [PMID:23499842]

7. Schümann J, Grevot A, Ledieu D, Wolf A, Schubart A, Piaia A, Sutter E, Côté S, Beerli C, Pognan F et al.. (2015) Reduced Activity of Sphingosine-1-Phosphate Lyase Induces Podocyte-related Glomerular Proteinuria, Skin Irritation, and Platelet Activation. Toxicol Pathol, 43 (5): 694-703. [PMID:25630683]

8. Weiler S, Braendlin N, Beerli C, Bergsdorf C, Schubart A, Srinivas H, Oberhauser B, Billich A. (2014) Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis. J Med Chem, 57 (12): 5074-84. [PMID:24809814]

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