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.
Paugh
Steven W
SW
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Payne
Shawn G
SG
Barbour
Suzanne E
SE
Milstien
Sheldon
S
Spiegel
Sarah
S
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