Vitamin B6 Effects on One-Carbon Metabolism

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DESCRIPTION (provided by applicant): Adequate vitamin B6 status is essential for health, and its coenzyme form (pyridoxal phosphate, PLP) is essential for several enzymes of one-carbon (1C) metabolism including serine hydroxymethyltransferase (SHMT), the glycine cleavage system (GCS), cystathionine R>-synthase (CBS), and cystathione-y-lyase (CGL). Homocysteine (Hey) is a central component in 1C metabolism subject to BG-dependent regulation via the PLP-dependence of remethylation and transsulfuration processes. However, there is little change in plasma Hey concentration in vitamin B6 deficiency. Mild hyperhomocysteinemia and low B6 status are each risk factors for cardiovascular disease and stroke, and the risk attributable to B6 deficiency is unrelated to plasma Hey. In our recent studies, mild to moderate B6 deficiency in humans caused 40% reduction in lymphocyte SHMT activity a key enzyme in generating 1C units. However, tracer kinetics indicated no impairment in fasting whole-body Hey remethylation, including B6-dependent remethylation with 1C units derived from serine via SHMT. Increased plasma glycine indicated that low B6 status caused functionally perturbed 1C metabolism, potentially because low B6 status caused reduced activities of SHMT and GCS. Increased plasma cystathionine indicated impaired transsulfuration due to reduced CGL activity. Rat studies showed that activities of SHMT and CGL, but not CBS, are reduced in even mild B6 deficiency. Since our previous infusions were conducted without a source of dietary amino acids, the rates of transsulfuration and other 1C reactions were minimal, which precluded observation of any effect of B6 status on transsulfuration. Static measurements also showed that B6 deficiency caused a small decrease in plasma cysteine and a 38% increase in plasma glutathione (GSH) concentration in human subjects. These findings are evidence of functional effects of marginal B6 deficiency on cysteine/GSH metabolism that require kinetic investigation for clarification. The proposed research involves stable isotope kinetic procedures and metabolite profile analysis to determine the functional impact of marginal vitamin B6 deficiency on glycine, serine and 1C metabolism, and on cysteine/GSH metabolism in healthy men and women. These studies will expand our understanding of the functional impact of vitamin B6 inadequacy and will yield new information regarding nutritional dependence of human 1C metabolism.