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

Abstract

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.