One‐Carbon Metabolic Kinetics in Human Disease Models

Abstract

The polymorphisms in MTHFR have been associated with altered risk of numerous human cancers whereas GNMT is commonly diminished in human hepatoma. Folate‐mediated one‐carbon metabolism is an important therapeutic target of many human diseases including cancer. We extensively investigated how gene‐nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes: MTHFR and GNMT. To further understand the metabolic roles of these genes in human disease progression, the biochemical impacts of gene alterations were carefully investigated: methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1‐carbon groups. The distinct model systems used included: EB virus‐transformed lymphoblasts expressing human polymorphic genotypes; liver‐derived transformed cell‐lines with and without overexpression of the target gene; and cells with stabilized inhibition using shRNA. We discovered that the genotype with reduced MTHFR function significantly reduces folate‐dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. Furthermore, GNMT affects transmethylation kinetics, S‐adenosylmethionine synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate‐dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over‐expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. Our systematic series of studies give new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention and progression.Support or Funding InformationMOST 104‐2320‐B005‐010‐MY3; MOST104‐2911‐I005‐301, Ministry of Education, Taiwan, R.O.C. under the ATU plan