title: A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis.
abstract: Folate-mediated one-carbon metabolism (FOCM) is an interconnected network of metabolic pathways, including those required for the de novo synthesis of dTMP and purine nucleotides and for remethylation of homocysteine to methionine. Mouse models of folate-responsive neural tube defects (NTDs) indicate that impaired de novo thymidylate (dTMP) synthesis through changes in SHMT expression is causative in folate-responsive NTDs. We have created a hybrid computational model comprised of ordinary differential equations and stochastic simulation. We investigated whether the de novo dTMP synthesis pathway was sensitive to perturbations in FOCM that are known to be associated with human NTDs. This computational model shows that de novo dTMP synthesis is highly sensitive to the common MTHFR C677T polymorphism and that the effect of the polymorphism on FOCM is greater in folate deficiency. Computational simulations indicate that the MTHFR C677T polymorphism and folate deficiency interact to increase the stochastic behavior of the FOCM network, with the greatest instability observed for reactions catalyzed by serine hydroxymethyltransferase (SHMT). Furthermore, we show that de novo dTMP synthesis does not occur in the cytosol at rates sufficient for DNA replication, supporting empirical data indicating that impaired nuclear de novo dTMP synthesis results in uracil misincorporation into DNA.
authors.affiliation: The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura, 1, 38068, Rovereto (TN), Italy.|Department of Mathematics, University of Trento, Trento, Italy.
authors.forename: Karla
authors.initials: K
authors.lastname: Misselbeck
authors.affiliation: The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura, 1, 38068, Rovereto (TN), Italy.
authors.forename: Luca
authors.identifier: http://orcid.org/0000-0001-9043-7705
authors.initials: L
authors.lastname: Marchetti
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York, 14853, USA.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Field
authors.affiliation: GEOMAR Helmholtz Centre for Ocean Research Kiel, Düsternbrooker Weg 20, 24105, Kiel, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Scotti
authors.affiliation: The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Piazza Manifattura, 1, 38068, Rovereto (TN), Italy. priami@cosbi.eu.|Department of Mathematics, University of Trento, Trento, Italy. priami@cosbi.eu.
authors.forename: Corrado
authors.initials: C
authors.lastname: Priami
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York, 14853, USA. pjs13@cornell.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000483:Alleles; D015415:Biomarkers; D002244:Carbon / Q000378:metabolism*; D004734:Energy Metabolism; D005492:Folic Acid / Q000378:metabolism*; D056726:Genetic Association Studies; D005838:Genotype; D053858:Metabolic Networks and Pathways; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D011110:Polymorphism, Genetic; D013269:Stochastic Processes; D013938:Thymidine Monophosphate / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D013938:Thymidine Monophosphate; D002244:Carbon; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)