Vitamin B6 nutritional status and cellular availability of pyridoxal 5′-phosphate govern the function of the transsulfuration pathway's canonical reactions and hydrogen sulfide production via side reactions

Abstract The transsulfuration pathway (TS) acts in sulfur amino acid metabolism by contributing to the regulation of cellular homocysteine, cysteine production, and the generation of H 2 S for signaling functions. Regulation of TS pathway kinetics involves stimulation of cystathionine β-synthase (CBS) by S-adenosylmethionine (SAM) and oxidants such as H 2 O 2 , and by Michaelis–Menten principles whereby substrate concentrations affect reaction rates. Although pyridoxal phosphate (PLP) serves as coenzyme for both CBS and cystathionine γ-lyase (CSE), CSE exhibits much greater loss of activity than CBS during PLP insufficiency. Thus, cellular and plasma cystathionine concentrations increase in vitamin B 6 deficiency mainly due to the bottleneck caused by reduced CSE activity. Because of the increase in cystathionine, the canonical production of cysteine (homocysteine → cystathionine → cysteine) is largely maintained even during vitamin B 6 deficiency. Typical whole body transsulfuration flux in humans is 3–7 μmol/h per kg body weight. The in vivo kinetics of H 2 S production via side reactions of CBS and CSE in humans are unknown but they have been reported for cultured HepG2 cells. In these studies, cells exhibit a pronounced reduction in H 2 S production capacity and rates of lanthionine and homolanthionine synthesis in deficiency. In humans, plasma concentrations of lanthionine and homolanthionine exhibit little or no mean change due to 4-wk vitamin B 6 restriction, nor do they respond to pyridoxine supplementation of subjects in chronically low-vitamin B 6 status. Wide individual variation in responses of the H 2 S biomarkers to such perturbations of human vitamin B 6 status suggests that the resulting modulation of H 2 S production may have physiological consequences in a subset of people. Supported by NIH grant DK072398. This paper refers to data from studies registered at clinicaltrials.gov as NCT01128244 and NCT00877812.