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This pathway illustrates the genes involved in mediating the effects of the
antimetabolite methotrexate, an analogue of reduced folate, which targets endogenous
cellular folate metabolism. At pharmacologic concentrations of 0.1 to 10mM, cellular
entry of methotrexate is by the reduced folate carrier (SLC19A1). Its main
intracellular target is dihydrofolate reductase (DHFR), inhibition of which results in
accumulation of dihydrofolate (DHF) and a depletion of cellular folates. Cytoplasmic
folylpolyglutamyl synthase (FPGS) adds glutamate residues to methotrexate; these larger
and more polar metabolites enhance activity by increasing intracellular retention, as
they are not substrates for folate transport systems, and by increasing the affinity
for target enzymes (TYMS, PPAT, GART and ATIC). Leucovorin (5-formyltetrahydrofolate)
is a reduced form of folic acid and can rescue cells by reversing these cytotoxic
effects of methotrexate.
The primary function of reduced folate is to provide single carbon donors for purine,
pyrimidine and amino acid synthesis, which are illustrated here in abbreviated schematics.
As folate plays a key role in DNA replication and cell division and is therefore
essential for metabolism, cells of all types will have at least some of the pathways
indicated. Expression of cellular transporters is partly tissue specific, for example
SLC22A6 and SLC22A8 are expressed in the kidney at levels ten times that of other
tissues. Intracellular localization is not indicated but is important for some targets,
for example GGH, which acts in lysosomes at low pH.
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Deborah French, Ph.D., Sharon Marsh, Ph.D., Leo Kager, M.D., Gianluigi Zaza, M.D.,
Cornelia Ulrich, Ph.D., Kathy Giacomini, Ph.D., Howard McLeod, Pharm.D., William Evans, Pharm.D.,
Mary V. Relling, Pharm.D.
St. Jude Children's Research Hospital, Memphis (PAAR Group); Fred Hutchinson Cancer
Research Center, Seattle; University of California at San Francisco (PMT Group);
Washington University, St. Louis (CREATE Group) |
| April 18, 2004 |
| December 20, 2007 |
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