title: The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity.
abstract: FTY720 is a novel immunomodulatory agent that inhibits lymphocyte trafficking and prevents allograft rejection. FTY720 is phosphorylated in vivo, and the phosphorylated drug acts as agonist for a family of G protein-coupled receptors that recognize sphingosine 1-phosphate. Evidence suggests that FTY720-phosphate-induced activation of S1P1 is responsible for its mechanism of action. FTY720 was rationally designed by modification of myriocin, a naturally occurring sphingoid base analog that causes immunosuppression by interrupting sphingolipid metabolism. In this study, we examined interactions between FTY720, FTY720-phosphate, and sphingosine-1-phosphate lyase, the enzyme responsible for irreversible sphingosine 1-phosphate degradation. FTY720-phosphate was stable in the presence of active sphingosine-1-phosphate lyase, demonstrating that the lyase does not contribute to FTY720 catabolism. Conversely, FTY720 inhibited sphingosine-1-phosphate lyase activity in vitro. Treatment of mice with FTY720 inhibited tissue sphingosine-1-phosphate lyase activity within 12 h, whereas lyase gene and protein expression were not significantly affected. Tissue sphingosine 1-phosphate levels remained stable or increased throughout treatment. These studies raise the possibility that disruption of sphingosine 1-phosphate metabolism may account for some effects of FTY720 on immune function and that sphingosine-1-phosphate lyase may be a potential target for immunomodulatory therapy.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California 94609-1673, USA.
authors.forename: Padmavathi
authors.initials: P
authors.lastname: Bandhuvula
authors.forename: Yuen Yee
authors.initials: YY
authors.lastname: Tam
authors.forename: Babak
authors.initials: B
authors.lastname: Oskouian
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008246:Lysophospholipids / Q000032:analysis / Q000378:metabolism; D051379:Mice; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D000068876:Fingolimod Hydrochloride; D013110:Sphingosine