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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Karla Misselbeck, Luca Marchetti, Martha S. Field, Marco Scotti, Corrado Priami, Patrick J. Stover
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ee1ba554942b4b4387b3ac00e7d20fca
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ee1ba554942b4b4387b3ac00e7d20fca
record_format	dspace
spelling	oai:doaj.org-article:ee1ba554942b4b4387b3ac00e7d20fca2021-12-02T12:32:06ZA hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis10.1038/s41598-017-00854-w2045-2322https://doaj.org/article/ee1ba554942b4b4387b3ac00e7d20fca2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00854-whttps://doaj.org/toc/2045-2322Abstract 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.Karla MisselbeckLuca MarchettiMartha S. FieldMarco ScottiCorrado PriamiPatrick J. StoverNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karla Misselbeck Luca Marchetti Martha S. Field Marco Scotti Corrado Priami Patrick J. Stover A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
description	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.
format	article
author	Karla Misselbeck Luca Marchetti Martha S. Field Marco Scotti Corrado Priami Patrick J. Stover
author_facet	Karla Misselbeck Luca Marchetti Martha S. Field Marco Scotti Corrado Priami Patrick J. Stover
author_sort	Karla Misselbeck
title	A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
title_short	A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
title_full	A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
title_fullStr	A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
title_full_unstemmed	A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis
title_sort	hybrid stochastic model of folate-mediated one-carbon metabolism: effect of the common c677t mthfr variant on de novo thymidylate biosynthesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ee1ba554942b4b4387b3ac00e7d20fca
work_keys_str_mv	AT karlamisselbeck ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT lucamarchetti ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT marthasfield ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT marcoscotti ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT corradopriami ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT patrickjstover ahybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT karlamisselbeck hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT lucamarchetti hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT marthasfield hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT marcoscotti hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT corradopriami hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis AT patrickjstover hybridstochasticmodeloffolatemediatedonecarbonmetabolismeffectofthecommonc677tmthfrvariantondenovothymidylatebiosynthesis
_version_	1718394191978954752

A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis

Ejemplares similares