The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2.
The potent immunosuppressive drug FTY720, a sphingosine analog, induces redistribution of lymphocytes from circulation to secondary lymphoid tissues. FTY720 is phosphorylated in vivo and functions as an agonist for four G-protein-coupled sphingosine-1-phosphate receptors. The identity of the kinase that phosphorylates FTY720 is still not known. Here we report that although both sphingosine kinase type 1 (SphK1) and type 2 (SphK2) can phosphorylate FTY720 with low efficiency, SphK2 is much more effective than SphK1. FTY720 inhibited phosphorylation of sphingosine catalyzed by SphK2 to a greater extent than it inhibits SphK1. Thus, SphK2 may be the relevant enzyme that is responsible for in vivo phosphorylation of FTY720.
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Steven W
SW
Paugh
Shawn G
SG
Payne
Suzanne E
SE
Barbour
Sheldon
S
Milstien
Sarah
S
Spiegel
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D017830:Octoxynol / Q000494:pharmacology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology; D013110:Sphingosine / Q000378:metabolism; D014162:Transfection; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D017830:Octoxynol; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase