Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism

Gregory, Jesse F.; Cuskelly, Geraldine; Shane, Barry; Toth, John P.; Baumgartner, Thomas G.; Stacpoole, Peter W.

doi:10.1093/ajcn/72.6.1535

Cited by 94 publications

(65 citation statements)

References 28 publications

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“…Both purine synthesis and oxidative release of carbon dioxide and THF by 10-formyl-THF dehydrogenase (EC 1.5.1.6) draw on the 10-formyl-THF pool. The irreversible and nonproductive dissipation of an excess in transferable one-carbon units is likely to be a significant regulatory factor, because the intrahepatic concentration of 10-formyl-THF exceeds the half-maximal equilibrium constant K m of 10-formyl-THF dehydrogenase (40). The 10-formyl-THF synthase activity of C-1-THF synthase, on the other hand, can add to the 5,10-methylene-THF pool by linking formate to free folate.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Kohlmeier

Costa

Fischer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

180

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Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0 -25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in premenopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a lowcholine diet.genetic polymorphism ͉ methylene tetrahydrofolate dehydrogenase ͉ methylene tetrahydrofolate reductase ͉ reduced folate carrier ͉ nutrient requirement

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Section: Discussionmentioning

confidence: 99%

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Kohlmeier

Costa

Fischer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

180

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“…An elegant stable isotope study in humans (55) provides further support for the role of mitochondrial one-carbon units in the remethylation of homocysteine. Gregory et al (55) showed that both cytoplasmic and mitochondrial one-carbon units end up in the methyl group of methionine following infusion of deuterated serine. This result strongly supports mitochondrial formate production as a significant contributor to cytoplasmic one-carbon units in vivo in mammals and places the mitochondrial C 1 -THF synthase in the center of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Human Mitochondrial C1-Tetrahydrofolate Synthase

Prasannan

Pike

Peng

et al. 2003

Journal of Biological Chemistry

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C 1 -tetrahydrofolate (THF) synthase is a trifunctional enzyme found in eukaryotes that contains the activities 10-formyl-THF synthetase, 5,10-methenyl-THF cyclohydrolase, and 5,10-methylene-THF dehydrogenase. The cytoplasmic isozyme of C 1 -THF synthase is well characterized in a number of mammals, including humans; but a mitochondrial isozyme has been previously identified only in the yeast Saccharomyces.

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“…Mitochondria contain a substantial portion of the cellular folate and some of the enzymes of the central cycle, namely SHMT, MTD, MTCH, FTD, and FTS (13,26). It is generally thought that mitochondria import serine from and export formate to the cytoplasm (18,38,90). Our basic model should be thought of as summing the folate cycles of cytoplasm and mitochondria.…”

Section: Folate-enzyme Binding and Homeostasismentioning

confidence: 99%

A Mathematical Model of the Folate Cycle

Nijhout

Reed

Budu

et al. 2004

Journal of Biological Chemistry

177

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A mathematical model is developed for the folate cycle based on standard biochemical kinetics. We use the model to provide new insights into several different mechanisms of folate homeostasis. The model reproduces the known pool sizes of folate substrates and the fluxes through each of the loops of the folate cycle and has the qualitative behavior observed in a variety of experimental studies. Vitamin B 12 deficiency, modeled as a reduction in the V max of the methionine synthase reaction, results in a secondary folate deficiency via the accumulation of folate as 5-methyltetrahydrofolate (the "methyl trap"). One form of homeostasis is revealed by the fact that a 100-fold up-regulation of thymidylate synthase and dihydrofolate reductase (known to occur at the G 1 /S transition) dramatically increases pyrimidine production without affecting the other reactions of the folate cycle. The model also predicts that an almost total inhibition of dihydrofolate reductase is required to significantly inhibit the thymidylate synthase reaction, consistent with experimental and clinical studies on the effects of methotrexate. Sensitivity to variation in enzymatic parameters tends to be local in the cycle and inversely proportional to the number of reactions that interconvert two folate substrates. Another form of homeostasis is a consequence of the nonenzymatic binding of folate substrates to folate enzymes. Without folate binding, the velocities of the reactions decrease approximately linearly as total folate is decreased. In the presence of folate binding and allosteric inhibition, the velocities show a remarkable constancy as total folate is decreased.The folate cycle plays a central role in cell metabolism. Among its important functions are the delivery of one-carbon units to the methionine cycle, for use in methylation reactions, and the synthesis of pyrimidines and purines. Dietary folate deficiency or genetic polymorphisms in folate-metabolizing enzymes are associated with megaloblastic anemia, developmental abnormalities including neural tube defects and Down's syndrome, and various types of cancer, especially those of the gastrointestinal tract and leukemias (1-8). Elevated homocysteine concentrations, a biomarker of a low folate status, have been implicated in cardiovascular diseases and Alzheimer's disease (6, 9, 10). Furthermore, several enzymes in the cycle are the targets of cancer chemotherapeutic agents (11, 12). Because of its importance in human health, folate metabolism has long been the focus of clinical, nutritional, and biochemical investigations. Biochemical studies have provided extensive and detailed information about each of the enzymes and metabolites of the folate cycle. As a consequence, the components and the reaction diagram of the folate cycle are well understood (13).The structure of the folate cycle is relatively complex (Fig. 1) and consists of several interacting loops. Most of the reactions depend in a nonlinear way on the concentrations of their substrates. Therefore, the behavior of the f...

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Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism

Cited by 94 publications

References 28 publications

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans

Human Mitochondrial C1-Tetrahydrofolate Synthase

A Mathematical Model of the Folate Cycle

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