Fig. 3: Mechanism of action of methotrexate.
From: Folate metabolism: a re-emerging therapeutic target in haematological cancers
Methotrexate (MTX) enters the cell mainly through the reduced folate carrier (RFC1) and to a lesser extend through receptor-mediated endocytosis via a folate receptor (FR). Upon entry, MTX gets polyglutamated (MTX(Glu)n) by folylpolyglutamate synthase (FPGS). Polyglutamates of MTX are a superior antifolate agent compared to MTX, capable of highly potent irreversible inhibition of DHFR. Furthermore, MTX induces inhibition of other enzymes like TYMS and GART/ATIC, ultimately blocking de novo thymidylate and purine syntheses. γ-glutamyl hydrolase (γ-GH) (compartmentalised in lysosomes) removes glutamate residues from MTX, while ATP-binding cassette (ABC) transporters assist in the excretion of MTX from the cell.
