Gregory Jesse F, DeRatt Barbara N, Rios-Avila Luisa, Ralat Maria, Stacpoole Peter W
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611-0370, USA.
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611-0370, USA.
Biochimie. 2016 Jul;126:21-6. doi: 10.1016/j.biochi.2015.12.020. Epub 2016 Jan 4.
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.
转硫途径（TS）在硫氨基酸代谢中发挥作用，有助于调节细胞内同型半胱氨酸、半胱氨酸的产生以及用于信号传导功能的H2S的生成。TS途径动力学的调节涉及S-腺苷甲硫氨酸（SAM）和氧化剂（如H2O2）对胱硫醚β-合酶（CBS）的刺激，以及根据米氏原理，底物浓度对反应速率的影响。尽管磷酸吡哆醛（PLP）是CBS和胱硫醚γ-裂解酶（CSE）的辅酶，但在PLP不足时，CSE的活性损失比CBS大得多。因此，维生素B6缺乏时，细胞和血浆中胱硫醚浓度升高主要是由于CSE活性降低导致的瓶颈效应。由于胱硫醚增加，即使在维生素B6缺乏时，半胱氨酸的经典生成途径（同型半胱氨酸→胱硫醚→半胱氨酸）在很大程度上仍得以维持。人类典型的全身转硫通量为每千克体重3 - 7 μmol/h。人类通过CBS和CSE的副反应产生H2S的体内动力学尚不清楚，但在培养的HepG2细胞中已有相关报道。在这些研究中，细胞在缺乏时H2S产生能力以及羊毛硫氨酸和高羊毛硫氨酸合成速率显著降低。在人类中，由于4周的维生素B6限制，血浆中羊毛硫氨酸和高羊毛硫氨酸的浓度几乎没有或没有平均变化，处于长期低维生素B6状态的受试者补充吡哆醇后它们也没有反应。H2S生物标志物对人类维生素B6状态这种扰动的反应存在广泛的个体差异，这表明由此导致的H2S产生调节可能在一部分人群中产生生理后果。由美国国立卫生研究院（NIH）资助项目DK072398支持。本文引用了在clinicaltrials.gov注册为NCT01128244和NCT00877812的研究数据。
