sphingosine-1-phosphate lyase 1 | Sphingosine 1-phosphate lyase | IUPHAR Guide to IMMUNOPHARMACOLOGY

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sphingosine-1-phosphate lyase 1

  Target has curated data in GtoImmuPdb

Target id: 2522

Nomenclature: sphingosine-1-phosphate lyase 1

Family: Sphingosine 1-phosphate lyase

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 568 10q21 SGPL1 sphingosine-1-phosphate lyase 1
Mouse - 568 10 B4 Sgpl1 sphingosine phosphate lyase 1
Rat - 568 20q11 Sgpl1 sphingosine-1-phosphate lyase 1
Previous and Unofficial Names
S1PL | Sphingosine-1-phosphate aldolase | SPL 1 | SP-lyase 1 | sphinganine-1-phosphate aldolase
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 4.1.2.27 Sphingosine 1-phosphate -> phosphoethanolamine + hexadecenal
dihydrosphingosine 1-phosphate -> phosphoethanolamine + hexadecanal
Cofactors
Cofactor Species Comments Reference
pyridoxal 5-phosphate None

Download all structure-activity data for this target as a CSV file

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] Hs Inhibition 6.7 pIC50 4-7
pIC50 6.7 (IC50 2.1x10-7 M) [4-7]
LX2931 Hs Inhibition <4.0 pIC50 7
pIC50 <4.0 (IC50 >1x10-4 M) [7]
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 [2], 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 [1,3,7].
Immuno Process Associations
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0030097 hemopoiesis IEA
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. 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]

2. 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]

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

4. 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]

5. 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]

6. 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]

7. 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]

How to cite this page

Sphingosine 1-phosphate lyase: sphingosine-1-phosphate lyase 1. Last modified on 05/02/2019. Accessed on 23/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2522.