Research Paper Volume 4, Issue 7 pp 480—498

Figure 2. Metformin treatment alters carbon flow through folate-related one-carbon metabolic pathways. (A) Diagram of tetrahydrofolate (THF)-dependent pathway of methionine trans-methylation to homocysteine and the trans-sulfuration pathway from homocysteine to glutathione (GSH) synthesis. MS, methionine synthase; SAH, S-adenosylhomocysteine; SAHH, SAH hydrolase; GSSG, oxidized glutathione disulfide; SAM, S-adenosylmethionine; MTase, methyltransferase. (B) Schematic depiction of purine and pyrimidine nucleotide biosynthesis through the de novo and salvage pathways. Because the biosynthetic pathways within the one-carbon network compete for a limiting pool of folate cofactors and folate-binding proteins can serve as “sinks” that sequester specific folates and thereby inhibit folate-dependent pathways, metformin-induced sequestration of 5-formimino-THF can simultaneously impairs the de novo nucleotide biosynthetic pathway while promoting GSH depletion. The conversion of thymidine and hypoxanthine to nucleotides via the folate-independent salvage pathway can partially rescue breast cancer cells from metformin's toxicity. TK, Thymidylate Kinase; HGPRT, hypoxanthine-guanine phosphoribosyltrans-ferase.