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 H2S for signaling functions. Regulation of TS pathway kinetics involves stimulation of cystathionine β-synthase (CBS) by S-adenosylmethionine (SAM) and oxidants such as H2O2, 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 B6 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 B6 deficiency. Typical whole body transsulfuration flux in humans is 3-7 μmol/h per kg body weight. The in vivo kinetics of H2S 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 H2S 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 B6 restriction, nor do they respond to pyridoxine supplementation of subjects in chronically low-vitamin B6 status. Wide individual variation in responses of the H2S biomarkers to such perturbations of human vitamin B6 status suggests that the resulting modulation of H2S 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.

Keywords: Cystathionine β-synthase; Cystathionine γ-lyase; Homolanthionine; Hydrogen sulfide; Lanthionine; One-carbon metabolism; Transsulfuration; Vitamin B(6).

Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Figures

Figure 1

Schematic model of the transsulfuration pathway illustrating relative concentrations and fluxes of reactions during vitamin B6 replete and deficient conditions. Major effects shown: (a) preferred reactions (canonical) are bold lines; (b) vitamin B6 deficiency causes a reduction in CSE activity from the reduced availability of cellular PLP (reduced quantity of active holo-CSE is designated by its reduced size); (c) CBS undergoes much less loss of activity during vitamin B6 deficiency; (d) cystathionine concentration is increased (greater font size) during vitamin B6 deficiency because of the bottleneck caused by reduced CSE activity, whereas cysteine production undergoes little change in deficiency because the higher cystathionine concentration compensates for the lower activity of CSE; (f) production of lanthionine and H2S is catalyzed mainly by CBS, which appears to exceed the CBS catalyzed production of H2S + cystathionine from homocysteine and cysteine. (g) production of H2S + homolanthionine is impaired in vitamin B6 deficiency due to the reduction in CSE activity (designated by smaller font); (e) CBS and CSE actually exist as tetramers (shown as monomeric holoenzymes in the figure).