A Mathematical Model Gives Insights into Nutritional and Genetic Aspects of Folate-Mediated One-Carbon Metabolism

Abstract

Impaired folate-mediated 1-carbon metabolism has been linked to multiple disease outcomes. A better understanding of the nutritional and genetic influences on this complex biochemical pathway is needed to comprehend their impact on human health. To this end, we created a mathematical model of folate-mediated 1-carbon metabolism. The model uses published data on folate enzyme kinetics and regulatory mechanisms to simulate the impact of genetic and nutritional variation on critical aspects of the pathway. We found that the model predictions match experimental data, while providing novel insights into pathway kinetics. Our primary observations were as follows: 1) the inverse association between folate and homocysteine is strongest at very low folate concentrations, but there is no association at high folate concentrations; 2) the DNA methylation reaction rate is relatively insensitive to changes in folate pool size; and 3) as folate concentrations become very high, enzyme velocities decrease. With regard to polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), the modeling predicts that decrease MTHFR activity reduces concentrations of S-adenosylmethionine and 5-methyltetrahydrofolate, as well as DNA methylation, while modestly increasing S-adenosylhomocysteine and homocysteine concentrations and thymidine or purine synthesis. Decreased folate together with a simulated vitamin B-12 deficiency results in decreases in DNA methylation and purine and thymidine synthesis. Decreased MTHFR activity superimposed on the B-12 deficiency appears to reverse the declines in purine and thymidine synthesis. These mathematical simulations of folate-mediated 1-carbon metabolism provide a cost-efficient approach to in silico experimentation that can complement and help guide laboratory studies.

Systems Biology of Phenotypic Robustness and Plasticity

“…2), in which metabolites activate or inhibit enzymes in the network. Our analysis has shown that these regulatory interactions serve to stabilize a few specific reactions in the system, namely: the TS reaction which is the rate-limiting step for DNA synthesis, the AICART reaction which is an early step in the de novo synthesis of nucleotides, the DNMT reaction which ensures correct methylation of newly replicated DNA, and also the synthesis of glutathione (not shown) (Nijhout et al 2004(Nijhout et al , 2006bReed et al 2006Reed et al , 2008. As amino acid input into the system varies, for instance with meals, these homeostatic mechanisms maintain stability of these critical reactions.…”

Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix

“…We observed that the degree or the pattern of global DNA methylation in tissues of the cervix is not altered by the fortification (1). A recently described mathematical simulation of folate-mediated 1-carbon metabolism (2) reported that intracellular methionine concentrations are relatively insensitive to variation in total folate, but intracellular concentration of S-adenosyl-methionine (SAM) had a strong linear association with total folate concentration suggesting that SAM concentrations are likely to be elevated due to higher folate intake as a result of the folic acid fortification. Even a short term supplementation with folic acid (1.2 mg/day for 12 week) has been shown to increase whole blood SAM in humans (3).…”

Evidence for Small Ubiquitin-like Modifier-dependent Nuclear Import of the Thymidylate Biosynthesis Pathway

“…Metabolic labeling studies, in vitro binding experiments, and mathematical modeling have indicated that methylene-THF is preferentially directed toward methionine synthesis relative to thymi-* This work was supported by Public Health Service Grant DK58144. The costs dylate biosynthesis (13,14). There is increasing evidence that the partitioning of methylene-THF between methionine and thymidylate synthesis is central to the origin of folate-related pathologies.…”