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...
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| Format: | Article |
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Nature Portfolio
2017-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-00854-w |
| _version_ | 1828959112110538752 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T09:01:41Z |
| format | Article |
| id | doaj.art-ee1ba554942b4b4387b3ac00e7d20fca |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T09:01:41Z |
| publishDate | 2017-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ee1ba554942b4b4387b3ac00e7d20fca2022-12-21T23:08:48ZengNature PortfolioScientific Reports2045-23222017-04-017111110.1038/s41598-017-00854-wA hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesisKarla Misselbeck0Luca Marchetti1Martha S. Field2Marco Scotti3Corrado Priami4Patrick J. Stover5The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI)The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI)Division of Nutritional Sciences, Cornell UniversityGEOMAR Helmholtz Centre for Ocean Research KielThe Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI)Division of Nutritional Sciences, Cornell UniversityAbstract 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.https://doi.org/10.1038/s41598-017-00854-w |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-00854-w |
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