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WIREs Syst Biol Med
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Modeling cellular compartmentation in one‐carbon metabolism

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Abstract Folate‐mediated one‐carbon metabolism (FOCM) is associated with risk for numerous pathological states including birth defects, cancers, and chronic diseases. Although the enzymes that constitute the biological pathways have been well described and their interdependency through the shared use of folate cofactors appreciated, the biological mechanisms underlying disease etiologies remain elusive. The FOCM network is highly sensitive to nutritional status of several B‐vitamins and numerous penetrant gene variants that alter network outputs, but current computational approaches do not fully capture the dynamics and stochastic noise of the system. Combining the stochastic approach with a rule‐based representation will help model the intrinsic noise displayed by FOCM, address the limited flexibility of standard simulation methods for coarse‐graining the FOCM‐associated biochemical processes, and manage the combinatorial complexity emerging from reactions within FOCM that would otherwise be intractable. WIREs Syst Biol Med 2013, 5:343–365. doi: 10.1002/wsbm.1209 This article is categorized under: Analytical and Computational Methods > Dynamical Methods Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease

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Compartmentation of folate‐mediated one‐carbon metabolism (FOCM) in the cytoplasm, mitochondrion, and nucleus. FOCM in the cytoplasm is required for the de novo synthesis of purines and thymidylate (dTMP), and for the remethylation of homocysteine to methionine. FOCM in the nucleus synthesizes dTMP from deoxyuridylate (dUMP) and serine. FOCM in mitochondrion is required to generate formate for FOCM in the cytoplasm, to generate and/or catabolize the amino acid glycine, and to synthesize dTMP. Enzyme abbreviations: AICAR Tfase, phosphoribosylaminoimidazolecarboxamide formyltransferase; CHF, 5,10‐methenyltetrahydrofolate; DHFR, dihydrofolate reductase; GAR Tfase, phosphoribosylglycinamide formyltransferase; GCS, glycine cleavage system; 5‐mTHF, 5‐methyltetrahydrofolate; MTHFD, methylenetetrahydrofolate dehydrogenase which may contain up to three enzymatic activities depending on the specific isozyme (see Figure 4): methenyltetrahydrofolate cyclohydrolase, 10‐formyltetrahydrofolate synthetase and methylenetetrahydrofolate dehydrogenase activities; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; SAH, S‐adenosylhomocysteine; SAM, S‐adenosylmethionine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; TYMS, thymidylate synthase; 10‐fTHF, 10‐formyltetrahydrofolate.

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Methylenetetrahydrofolate dehydrogenase (MTHFD1) is a trifunctional enzyme with three enzymatic activities methenyltetrahydrofolate cyclohydrolase, 10‐formyltetrahydrofolate synthetase, and methylenetetrahydrofolate dehydrogenase. The MTHFD1L isozyme only exhibits 10‐formyltetrahydrofolate synthetase, whereas the MTHFD2 and MTHFD2L isozymes only exhibit methenyltetrahydrofolate cyclohydrolase and methylenetetrahydrofolate dehydrogenase activities. THF, tetrahydrofolate; 10‐fTHF, 10‐formyltetrahydrofolate; CHF, 5,10‐methenyltetrahydrofolate.

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Regulation of cytoplasmic folate‐activated one‐carbon pools. The relative distribution of one‐carbon activated forms of THF is regulated by folate‐binding proteins and one‐carbon depleting reactions. FDH, 10‐formyltetrahydofolate dehydrogenase ; MTHFS, methenyltetrahydrofolate synthetase; SHMT, serine hydroxymethyltransferase; GNMT, glycine N‐methyltransferase. THF, tetrahydrofolate; 10‐fTHF, 10‐formyltetrahydrofolate; CHF, 5,10‐methenyltetrahydrofolate; 5‐mTHF, 5‐methyltetrahydrofolate.

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De novo purine nucleotide biosynthesis is a 10‐step pathway in the cytoplasm that functions as a multienzyme complex referred to as a purinosome. Reactions 3 and 9 require 10‐formyltetrahydrofolate as a cofactor. Enzyme abbreviations: AICAR Tfase, phosphoribosylaminoimidazole carboxamide formyltransferase; AIRS, aminoimidazole ribonucleotide synthetase; ASL, adenylosuccinate lyase; CAIRS, carboxyaminoimidazole ribonucleotide synthase; FGAMS, phosphoribosylformylglycinamidine synthase; GARS, glycinamide ribonucleotide synthetase; GAR Tfase, phosphoribosylglycinamide formyltransferase; HPRT, hypoxanthine phosphoribosyl transferase; IMPCH, IMP cyclohydrolase; PPAT, PRPP amidotransferase; SAICARS, succinylaminoimidazolecarboxamide ribonucleotide synthetase.

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