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Methodology and Mathematical Modeling

A Mathematical Model Gives Insights into the Effects of Vitamin B-6 Deficiency on 1-Carbon and Glutathione Metabolism^1–3,

⁴ Department of Biology, Duke University, Durham, NC 27708; ⁵ Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611; ⁶ Department of Mathematics, Duke University, Durham, NC 27708; ⁷ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and ⁸ University of Washington, Department of Epidemiology and Interdisciplinary Graduate Program in the Nutrition Sciences, Seattle, WA 98195

We experimented with a mathematical model for 1-carbon metabolism and glutathione (GSH) synthesis to investigate the effects of vitamin B-6 deficiency on the reaction velocities and metabolite concentrations in this metabolic network. The mathematical model enabled us to independently alter the activities of each of the 5 vitamin B-6–dependent enzymes and thus determine which inhibitions were responsible for the experimentally observed consequences of a vitamin B-6 deficiency. The effect of vitamin B-6 deficiency on serine and glycine concentrations in tissues and plasma was almost entirely due to its effects on the activity of glycine decarboxylase. The effect of vitamin B-6 restriction on GSH concentrations appeared to be indirect, arising from the fact that vitamin B-6 restriction increases oxidative stress, which, in turn, affects several enzymes in 1-carbon metabolism as well as the GSH transporter. Vitamin B-6 restriction causes an abnormally high and prolonged homocysteine response to a methionine load test. This effect appeared to be mediated solely by its effects on cystathionine β-synthase. Reduction of the enzymatic activity of serine hydroxymethyltransferase (SHMT) had negligible effects on most metabolite concentrations and reaction velocities. Reduction or total elimination of cytoplasmic SHMT had a surprisingly moderate effect on metabolite concentrations and reaction velocities. This corresponds to the experimental findings that a reduction in the enzymatic activity of SHMT has little effect on 1-carbon metabolism. Our simulations showed that the primary function of SHMT was to increase the rate by which the glycine-serine balance was reequilibrated after a perturbation.

^* To whom correspondence should be addressed. E-mail: hfn{at}duke.edu.

Manuscript received 5 January 2009. Initial review completed 12 January 2009. Revision accepted 30 January 2009.

Published online 25 February 2009.

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