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Nijhout, H.F. et al.

H. Frederik Nijhout, Jesse F. Gregory, Courtney Fitzpatrick, Eugenia Cho, K. Yvonne Lamers, Cornelia M. Ulrich, Michael C. Reed,

A mathematical model gives insights into the effects of vitamin B-6 deficiency on 1-carbon and glutathione metabolism.

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 beta-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.[1]

References

A mathematical model gives insights into the effects of vitamin B-6 deficiency on 1-carbon and glutathione metabolism. Nijhout, H.F., Gregory, J.F., Fitzpatrick, C., Cho, E., Lamers, K.Y., Ulrich, C.M., Reed, M.C. J. Nutr. (2009) [Pubmed]

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