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.
Highlights
Perturbations in folate-mediated one-carbon metabolism (FOCM) are associated with numerous pathologies including neural tube defects (NTDs)[1], stroke[2], colorectal and other types of cancer[3,4,5]
We explored the impact of the MTHFR C677T polymorphism and its interaction with folate status on partitioning of CH2F within the network, including its impact on de novo dTMP biosynthesis to understand the etiology of NTDs
MTHFR activity was decreased to model the effect of the MTHFR C677T polymorphism
Summary
Perturbations in folate-mediated one-carbon metabolism (FOCM) are associated with numerous pathologies including neural tube defects (NTDs)[1], stroke[2], colorectal and other types of cancer[3,4,5]. Using data from experimental animals, non-trivial mathematical functions were adopted to address long-range inhibition and activation processes involving folates and other metabolites that cannot be translated into simple Michaelis-Menten equations[17] These models can reproduce changes in metabolite concentrations in response to nutritional deficiencies and the effects of gene variants, corroborating human clinical and epidemiological data. In contrast to approaches based solely on deterministic simulation, these studies can be used to assess the contributions of factors such as genetic variation and nutritional status on the stochastic behavior of individual pathways within the network, thereby aiding in establishing which system inputs (i.e. nutrition) and outputs (i.e. biomarkers) are most closely associated with human health outcomes. The variant results from an alanine to valine substitution in the protein that decreases MTHFR
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.