FTY720-phosphate is dephosphorylated by lipid phosphate phosphatase 3.
FTY720 is a novel immunomodulatory drug efficacious in the treatment of multiple sclerosis. The drug is converted in vivo to the monophosphate, FTY720-P, by sphingosine kinase 2. This conversion is incomplete, suggesting opposing actions of kinase and phosphatase activities. To address which of the known lipid phosphatases might dephosphorylate FTY720-P, we overexpressed the broad specificity lipid phosphatases LPP1-3, and the specific S1P phosphatases (SPP1 and 2) in HEK293 cells, and performed in vitro assays using lysates of transfected cells. Among LPPs, only LPP3 was able to dephosphorylate FTY720-P; among SPPs, only SPP1 showed activity against FTY720-P. On intact cells, LPP3 acted as an ecto-phosphatase or FTY720-P, thus representing the major phosphatase involved in the equilibrium between FTY720 and FTY720-P observed in vivo.
Mechtcheriakova
Diana
D
Novartis Institutes for BioMedical Research, Vienna, Austria.
Wlachos
Alexander
A
Sobanov
Jury
J
Bornancin
Frederic
F
Zlabinger
Gerhard
G
Baumruker
Thomas
T
Billich
Andreas
A
D002478:Cells, Cultured; D000068876:Fingolimod Hydrochloride; D006801:Humans; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000737:chemistry / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D010710:Phosphates; D011409:Propylene Glycols; C112948:lipid phosphate phosphatase; C521833:PLPP3 protein, human; D010711:Phosphatidate Phosphatase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine