Sphingosine 1-phosphate lyase

Bandhuvula P, Saba JD. Sphingosine-1-phosphate lyase in immunity and cancer silencing the siren. Trends Molec. Pharmacol. 2007 66 1671-1678. 

HPR-mediated leukemia cell c)4otoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2. Free Radical Res. 2007 41 591-601. Wang H, Maurer BJ, Reynolds CP, Cabot MC. N-(4-Hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res. 2001 61 5102-5105. Bandhuvula P, Tam YY, Oskouian B, Saba JD. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J. Biol. Chem. 2005 280 33697-33700. 

Boumendjel A, Miller SPF. Synthesis of an inhibitor of sphingosine-1-phosphate lyase. Tetrahedron Lett. 1994 35 819-822. 

Kihara A, Ikeda M, Kariya Y, Lee EY, Lee YM, Igarashi Y (2003) Sphingosine-1-phosphate lyase is involved in the differentiation of F9 embryonal carcinoma cells to primitive endoderm. J Biol Chem 278 14578-14585... 

Li G, Foote C, Alexander S, Alexander H (2001) Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum. Development 128 3473-3483... 

Keywords Acid sphingomyelinase eeramide sphingosine kinase sphingosine-1-phosphate lyase sphingosine-1-phosphate... 

Sphingosine-1-Phosphate Lyase as Novel Target in Tmmunmodulation... 

Sphingosine-1-phosphate lyase (SPL) is the enzyme responsible for the irreversible cleavage of SIP in a retroaldol reaction to yield hexadecenal and phos-phoethanolamine as degradation products. The enzyme, therefore, is in a critical position to regulate levels of SIP (Bandhuvula and Saba, 2007). Here, we will focus on recent evidence that SPL may serve as a target for modulation of immune responses in transplantation settings and in the treatment of autoimmune disease. 

Bandhuvula, P., Tam, Y.Y., Oskouian, B., and Saba, J.D., The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity, J Biol Chem, 280 (2005) 33697-36700. 

Stoffel, W. Bauer, E. Stahl, J. The metabolism of sphingosine bases in Te-trahymena pyriformis. Sphingosine kinase and sphingosine-1-phosphate lyase. Hoppe-Seyler s Z. Physiol. Chem., 355, 61-74 (1974)... 

D-Fructosamine undergoes Buchi cyclocondensation reaction with nitriles, providing access to a variety of disubstituted imidazoles (Scheme 45), some of which have been proposed as potential sphingosine-1-phosphate lyase inhibitors for the treatment of such autoimmune disorders as rheumatoid arthritis or multiple sclerosis. 

During the synthesis of sphingosine-1-phosphate lyase (SIPL) inhibitor for the treatment of autoimmune disorders, Bagdanoff and co-workers prepared the a,a-difluoro analog of 2-acetyl-4(5)-[l(f ),2(5),3(f ),4-tetrahydroxybutyl]imidazole (Scheme 20) [30], Ketalization of the diol using 2,2-dimethoxypropane followed by the treatment of bisketal with DAST and subsequent deprotection afforded the targeted 2-(l,l-difluoroethyl)imidazole derivative. 

Zhou, J. and Saba, J., 1998, Identification of the first mammalian sphingosine phosphate lyase gene and its fimctional expression in yeast, Biochim. Biophys. Res. Comm. 242 502-507. 

Reiss U, Oskouian B, Zhou J, Gupta V, Sooriyakumaran P, Kelly S, Wang E, Merrill AH Jr, Saba JD. Sphingosine-phosphate lyase enhances stress-induced ceramide generation and apoptosis. J. Biol. Chem. 2004 279 1281-1290. 

Mendel J, Heinecke K, Eyrst H, Saba JD (2003) Sphingosine phosphate lyase expression is essential for normal development in Caenorhabditis elegans. J Biol Chem 278 22341-22349... 

Sphingosine is catabolized to rrans-2-hexadecanal and phosphoethanolamine by way of sphingosine phosphate and its cleavage by a lyase. Catabolism of glycosphingolipids involves removal of successive glycosyl residues from their nonreducing end until ceramide is released. 

Min, J., Van Veldhoven, P.P., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. Sphingosine-l-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent maimer. Mol Cancer Res, 3, 2005, 287-296. 

Van Veldhoven, PP (2000) Sphingosine-l-phosphate lyase. Methods Enzymol, 311, 244-254. 

SIP is formed from sphingosine by sphingosine kinases (SphKs). Degradation of SIP occurs either reversibly by lipid phosphate phosphohydrolases (LPPs) and SIP phosphatases (SPPs), or irreversibly by SIP lyase (SPL) (Fig. 1). The localization of SIP production is highly important since SIP plays a role both as extracellular mediator and as intracellular... 

---