THI (2-Acetyl-5-tetrahydroxybutyl imidazole) inhibits the enzyme activity in intact cell preparations [4].
Recessive mutations in the S1P lyase (SGPL1) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS) [1].
A Phase 2 clinical trial of LX3305 (LX2931) for rheumatoid arthritis has been completed (see NCT00903383).

* Key recommended reading is highlighted with an asterisk

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]

* Bamborschke D, Pergande M, Becker K, Koerber F, Dötsch J, Vierzig A, Weber LT, Cirak S. (2018) A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation. Brain Dev., 40 (6): 480-483. [PMID:29501407]

Bigaud M, Guerini D, Billich A, Bassilana F, Brinkmann V. (2014) Second generation S1P pathway modulators: research strategies and clinical developments. Biochim. Biophys. Acta, 1841 (5): 745-58. [PMID:24239768]

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]

* Choi YJ, Saba JD. (2019) Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. Adv Biol Regul, 71: 128-140. [PMID:30274713]

Ebenezer DL, Fu P, Natarajan V. (2016) Targeting sphingosine-1-phosphate signaling in lung diseases. Pharmacol. Ther., 168: 143-157. [PMID:27621206]

* Lovric S, Goncalves S, Gee HY, Oskouian B, Srinivas H, Choi WI, Shril S, Ashraf S, Tan W, Rao J et al.. (2017) Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J. Clin. Invest., 127 (3): 912-928. [PMID:28165339]

* Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergadá I et al.. (2017) Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J. Clin. Invest., 127 (3): 942-953. [PMID:28165343]

Sanllehí P, Abad JL, Casas J, Delgado A. (2016) Inhibitors of sphingosine-1-phosphate metabolism (sphingosine kinases and sphingosine-1-phosphate lyase). Chem. Phys. Lipids, 197: 69-81. [PMID:26200919]

Van Veldhoven PP, Gijsbers S, Mannaerts GP, Vermeesch JR, Brys V. (2000) Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). Biochim. Biophys. Acta, 1487 (2-3): 128-34. [PMID:11018465]

1. Choi YJ, Saba JD. (2019) Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. Adv Biol Regul, 71: 128-140. [PMID:30274713]

2. 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]

3. 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]

4. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG. (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science, 309 (5741): 1735-9. [PMID:16151014]

5. 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]

6. 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]

Nigel J Pyne Strathclyde Institute of Pharmacy and Biomedical Science University of Strathclyde 161 Cathedral Street Glasgow G4 0RE, UK Susan Pyne Strathclyde Institute of Pharmacy and Biomedical Science University of Strathclyde 161 Cathedral Street Glasgow G4 0RE, UK