Methionine synthase is essential for cancer cell proliferation in physiological folate environments

Abstract

Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples the folate and methionine metabolic cycles, methionine synthase (MTR), is required for cancer cell proliferation and tumor growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, MTR incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.

Cloning of a novel tetrahydrofolate-dependent dicamba demethylase gene from dicamba-degrading consortium and characterization of the gene product

“…Compared with DMO, the advantage of the THF-dependent demethylases Dmt and Dmt50 is that they do not need reducing force NADH, so it is more energy-saving. In addition, the 5-methyl-THF generated during dicamba demethylation can be used for the synthesis of purine, pyrimidine, glycine and methionine, as well as the methylation of DNA, fatty acids and enzymes ( Sullivan et al, 2021 ; Menezo et al, 2022 ). However, the disadvantage of Dmt and Dmt50 is that their activities were lower than that of DMO, which greatly limits their abilities to detoxify dicamba.…”

Simplifying the B Complex: How Vitamins B6 and B9 Modulate One Carbon Metabolism in Cancer and Beyond

“…Importantly, the high consumption of methionine outcompetes regeneration and renders these cancer cells auxotrophic to methionine and vulnerable to pharmacological inhibition [ 240 ] ( Figure 6 ). Similarly, genetic mutations in one carbon metabolic enzyme methyl-5′-thioadenosine phosphorylase (MTAP) offer a point to help identify tumor cell populations that could be vulnerable to reducing dietary methionine [ 241 , 242 , 243 , 244 ]. The mechanism for this underlies the methionine salvage pathway and the generation of metabolite MTA, which acts as an inhibitor of methylation.…”

Folate Metabolism in Hepatocellular Carcinoma. What Do We Know So Far?

“…Folate is required to convert homocysteine to methionine in the methionine pathway. In this process, MTR plays a central role in SAM production, and recently Sullivan et al 85 proved the implication of MTR activity and cancer cell proliferation. On the other hand, inadequate SAM production can lead to decreased methylation of CpG islands in DNA, which affects gene transcription and alters the expression of tumor suppressor genes and proto-oncogenes.…”