After the initial use of anti-folates for treatment of malignancies, folate metabolism has emerged as a rational diagnostic and therapeutic target in gastrointestinal cancer. The one-carbon metabolic pathway, which comprises three critical reactions (i.e., folate and methionine cycles), underlies this effect in conjunction with the trans-sulfuration pathway. Understanding of the one-carbon metabolism pathway has served to unravel the link between the causes and effects of cancer phenotypes leading to several seminal discoveries such as that of diadenosine tri-phosphate hydrolase, microRNAs, 5-FU and, more recently, trifluridine. In the folate cycle, glycine and serine fuel the mitochondrial enzymes SHMT2, MTHFD2 and ALDH1L2, which play critical roles in the cancer survival and proliferation presumably through purine production. In the methionine cycle, S-adenocyl methionine serves hydrocarbons and polyamines that are critical for the epigenetic controls. The trans-sulfuration pathway is a critical component in the synthesis of glutathione, which is involved in the production of reactive oxygen species in cancer stem cells. Therefore, characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. In the present study, we review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.
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