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 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.

Vitamin B-6 restriction tends to reduce the red blood cell glutathione synthesis rate without affecting red blood cell or plasma glutathione concentrations in healthy men and women

“…Thus, the effect of marginal 1 All values are means 6 SEMs; n = 13. vitamin B-6 deficiency on RBC glutathione synthesis rates appeared to be unrelated to the supply of the precursor amino acid cysteine. This finding is consistent with recent results of mathematical modeling simulations that predicted the effect of mild vitamin B-6 deficiency on blood glutathione concentration to be solely related to increased oxidative stress and not to the reduced velocity of PLP-dependent enzymes involved in cysteine formation (45). The variability in responses among subjects might result from factors influencing the activity and expression of c-glutamyl-cysteine-synthetase, eg antioxidants and hormones such as insulin and glucocorticoids (1).…”

Pyridoxine supplementation does not alter in vivo kinetics of one-carbon metabolism but modifies patterns of one-carbon and tryptophan metabolites in vitamin B-6–insufficient oral contraceptive users

“…Studies in animals and humans and mathematical modeling have shown effects of vitamin B-6 deficiency on several aspects of metabolism that are consistent with the multiple metabolic functions of PLP (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Our previous studies showed that low vitamin B-6 status with a plasma PLP concentration ,30 nmol/L, which is consistent with marginal deficiency (26), also induces metabolic effects including alterations in concentrations of certain constituents of one-carbon and tryptophan pathways (17,18,20,27).…”

“…Increased glycine has been reported in liver (49,50), muscle, and plasma of vitamin B-6-deficient rats (50,51), in the plasma of vitamin B-6-deficient humans (16,18,20,23), and in vitamin B-6restricted cultured cells (52), concurrent with modeling predictions (24). Major processes for the metabolism of glycine include PLP-dependent reactions catalyzed by serine hydroxymethyltransferase isoforms and by glycine decarboxylase in the glycine cleavage system (53).…”

Methylation Status and Neurodegenerative Markers in Parkinson Disease

“…Vitamin B 6 enhances the direct flow of tHcy via cystathionine ␤-synthase and cystathionine ␥-lyase into cysteine, the precursor of glutathione (24 ). Vitamin B 6 deficiency induces oxidative stress, which in turn affects several enzymes in 1-carbon metabolism, thus indirectly causing lower glutathione (25 ). In addition, vitamin B 6 is a cofactor for serine hydroxymethyl transferase, a folate catabolizing enzyme.…”