Fig. 1

Mechanism of action MTX and LV. Overview of the folate pathway with separate folate isoforms and converting enzymes in relation to the mechanism of action of MTX. MTX enters the cell through RFC1, PCFT and MFR. MTX is then polyglutamated (−PG) by FPGS and depolyglutamated by GGH, after which MTX is exported out of the cell by ABC transporters. MTX(−PG) inhibits TS and DHFR. Leucovorin (5-formylTHF) is represented in bold / italic and bypasses the action of DHFR. Abbreviations: ABCB1 - ATP Binding Cassette Subfamily B Member 1; ABCC1–4 - ATP Binding Cassette Subfamily C Member 1–4; ABCG2 - ATP Binding Cassette Subfamily G Member 2; DHF – Dihydrofolate; DHFR – Dihydrofolate Reductase; FPGS – Folylpolyglutamate Synthetase; GGH – Gamma-Glutamyl Hydrolase; MFR – Membrane Folate Transporter; MTHFR - Methylene tetrahydrofolate reductase; MTHFD1 - Methylenetetrahydrofolate Dehydrogenase, Cyclohydrolase And Formyltetrahydrofolate Synthetase 1; PCFT – Proton-Coupled Folate Transporter; RFC1 – Reduced Folate Carrier; SHMT - Serine hydroxymethyltransferase; THF – tetrahydrofolate; TS – Thymidylate Synthase. This Figure was created using Microsoft Office Powerpoint