Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
 2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Folate-dependent one-carbon metabolism is required for the synthesis of purines and thymidylate and for the remethylation of homocysteine to methionine. Methionine is subsequently adenylated to S-adenosylmethionine (SAM), a cofactor that methylates DNA, RNA, proteins, and many metabolites. Previous experimental and theoretical modeling studies have indicated that folate cofactors are limiting for cytoplasmic folate-dependent reactions and that the synthesis of DNA precursors competes with SAM synthesis. Each of these studies concluded that SAM synthesis has a higher metabolic priority than dTMP synthesis. The influence of cytoplasmic serine hydroxymethyltransferase (cSHMT) on this competition was examined in MCF-7 cells. Increases in cSHMT expression inhibit SAM concentrations by two proposed mechanisms: (1) cSHMT-catalyzed serine synthesis competes with the enzyme methylenetetrahydrofolate reductase for methylenetetrahydrofolate in a glycine-dependent manner, and (2) cSHMT, a high affinity 5-methyltetrahydrofolate-binding protein, sequesters this cofactor and inhibits methionine synthesis in a glycine-independent manner. Stable isotope tracer studies indicate that cSHMT plays an important role in mediating the flux of one-carbon units between dTMP and SAM syntheses. We conclude that cSHMT has three important functions in the cytoplasm: (1) it preferentially supplies one-carbon units for thymidylate biosynthesis, (2) it depletes methylenetetrahydrofolate pools for SAM synthesis by synthesizing serine, and (3) it sequesters 5-methyltetrahydrofolate and inhibits SAM synthesis. These results indicate that cSHMT is a metabolic switch that, when activated, gives dTMP synthesis higher metabolic priority than SAM synthesis.
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PMID:Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. 1216 34

Glycine specifically induces genes encoding subunits of the glycine decarboxylase complex (GCV1, GCV2, and GCV3), and this is mediated by a fall in cytoplasmic levels of 5,10-methylenetetrahydrofolate caused by inhibition of cytoplasmic serine hydroxymethyltransferase. Here it is shown that this control system extends to genes for other enzymes of one-carbon metabolism and de novo purine biosynthesis. Northern analysis of the response to glycine demonstrated that the induction of the GCV genes and the induction of other amino acid metabolism genes are temporally distinct. The genome-wide response to glycine revealed that several other genes are rapidly co-induced with the GCV genes, including SHM2, which encodes cytoplasmic serine hydroxymethyltransferase. These results were refined by examining transcript levels in an shm2Delta strain (in which cytoplasmic 5,10-methylenetetrahydrofolate levels are reduced) and a met13Delta strain, which lacks the main methylenetetrahydrofolate reductase activity of yeast and is effectively blocked at consumption of 5,10-methylene tetrahydrofolate for methionine synthesis. Glycine addition also caused a substantial transient disturbance to metabolism, including a sequence of changes in induction of amino acid biosynthesis and respiratory chain genes. Analysis of the glycine response in the shm2Delta strain demonstrated that apart from the one-carbon regulon, most of these transient responses were not contingent on a disturbance to one-carbon metabolism. The one-carbon response is distinct from the Bas1p purine biosynthesis regulon and thus represents the first example of transcriptional regulation in response to activated one-carbon status.
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PMID:Identification of a novel one-carbon metabolism regulon in Saccharomyces cerevisiae. 1464 32

Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.
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PMID:Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men. 1604 27