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

• Published in: Biochimie Vol. 126; pp. 21 - 26
• Main Authors: Gregory, Jesse F., DeRatt, Barbara N., Rios-Avila, Luisa, Ralat, Maria, Stacpoole, Peter W.
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01.07.2016
• Subjects: amino acid metabolism; Animals; biomarkers; Clinical Trials as Topic; cystathionine; cystathionine beta-synthase; cystathionine gamma-lyase; Cystathionine β-synthase; Cystathionine γ-lyase; cysteine; Female; Hep G2 Cells; homocysteine; Homolanthionine; human cell lines; Humans; hydrogen peroxide; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Lanthionine; Male; Nutritional Status; One-carbon metabolism; oxidants; pyridoxal; pyridoxal phosphate; Pyridoxal Phosphate - metabolism; pyridoxine; S-adenosylmethionine; Transsulfuration; Vitamin B 6 - metabolism; Vitamin B6; Hydrogen sulfide; Cystathionine γ-lyase; CSE; PLP; CBS; Lanthionine; Homolanthionine; H2S; One-carbon metabolism; Cystathionine β-synthase; Transsulfuration; Vitamin B6; Vitamin B
• ISSN: 0300-9084; 1638-6183; 1638-6183
• DOI: 10.1016/j.biochi.2015.12.020

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. •Transsulfuration enzymes, CBS and CSE, bind the coenzyme PLP with similarly high affinity.•Vitamin B6 deficiency corresponds with a significant reduction in the activity of CSE but minimally effects CBS activity.•Cystathionine elevation tends to maintain the flux of cysteine production by CSE even during low cellular PLP conditions.•Production of lanthionine and homolanthionine can serve as surrogate markers of H2S production.•Low cellular PLP reduces H2S production capacity and corresponding synthesis of lanthionine and homolanthionine.