Division of labour: how does folate metabolism partition between one-carbon metabolism and amino acid oxidation?

Abstract

One-carbon metabolism is usually represented as having three canonical functions: purine synthesis, thymidylate synthesis and methylation reactions. There is however a fourth major function: the metabolism of some amino acids (serine, glycine, tryptophan and histidine), as well as choline. These substrates can provide cells with more one-carbon groups than they need for these three canonical functions. Therefore, there must be mechanisms for the disposal of these one-carbon groups (when in excess) which maintain the complement of these groups required for the canonical functions. The key enzyme for these mechanisms is 10-formyl-THF (tetrahydrofolate) dehydrogenase (both mitochondrial and cytoplasmic isoforms) which oxidizes the formyl group to CO2 with the attendant reduction of NADP(+) to NADPH and release of THF. In addition to oxidizing the excess of these compounds, this process can reduce substantial quantities of NADP(+) to NADPH.

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

“…The importance of serine and glycine as precursors in those processes is comprehensively summarized in the review by Amelio and coworkers [22]. Briefly, both serine and glycine contribute to cellular metabolism through the glycine cleavage system, which refuels one-carbon metabolism based on chemical reactions of folate compounds [23]. The importance of folate metabolism is underlined by the fact that antifolate chemotherapy is currently widely used in cancer treatment [24].…”

Serine one-carbon catabolism with formate overflow

“…Glycine or formate release could be due to the one-to-one ratio of glycine and one-carbon unit production from serine but different biosynthetic demands of glycine and one-carbon units ( 11 ). To reduce the biosynthetic demands and their potential imbalances, we switched to a culture medium where glucose was replaced by galactose.…”

One-Carbon Metabolism in Health and Disease

“…Folate metabolism is a major contributor to amino acid homeostasis (Brosnan et al, 2015). Isotopic tracer infusion studies in humans illustrate the high total body turnover in 1C-related amino acids.…”