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

* 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]

* Schwiebs A, Herrero San Juan M, Schmidt KG, Wiercinska E, Anlauf M, Ottenlinger F, Thomas D, Elwakeel E, Weigert A, Farin HF et al.. (2019) Cancer-induced inflammation and inflammation-induced cancer in colon: a role for S1P lyase. Oncogene, 38 (24): 4788-4803. [PMID:30816345]

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. 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. 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]

3. 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]

4. 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]

5. 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]

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]

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