Vitamin B6 Effects on One-Carbon Metabolism

说明(申请人提供)：充足的维生素B6状态对健康至关重要，其辅酶形式(磷酸吡哆醛，PLP)是一碳(1C)代谢的几种酶所必需的，包括丝氨酸羟甲基转移酶(SHMT)、甘氨酸裂解系统(GCS)、胱硫氨酸R&GT合酶(CBS)和胱硫酮-y-裂解酶(CGL)。同型半胱氨酸(Hcy)是1C代谢的中心成分，通过依赖PLP的再甲基化和转硫化过程受到BG依赖的调节。但维生素B6缺乏症患者的血浆HY浓度变化不大。轻度高同型半胱氨酸血症和低B6状态都是心血管疾病和中风的危险因素，而B6缺乏的风险与血浆HY无关。在我们最近的研究中，人类轻度到中度的B6缺乏导致淋巴细胞SHMT活性下降40%，这是产生1C单位的关键酶。然而，示踪剂动力学表明，禁食全身Hy的重新甲基化没有损害，包括通过SHMT从丝氨酸衍生的1C单位的B6依赖的重新甲基化。血浆甘氨酸升高表明低B6状态导致1C代谢功能紊乱，可能是因为低B6状态导致SHMT和GCS活性降低。血浆半胱硫氨酸升高表明CGL活性降低导致硫磺转导功能受损。老鼠研究表明，即使是轻微的B6缺乏，SHMT和CGL的活性也会降低，但CBS的活性不会降低。由于我们之前的输液是在没有膳食氨基酸来源的情况下进行的，因此转硫率和其他1C反应很小，这排除了观察到B6状态对转硫率的任何影响。静态测量还显示，B6缺乏导致受试者血浆半胱氨酸略有下降，血浆谷胱甘肽(GSH)浓度上升38%。这些发现是边际B6缺乏对半胱氨酸/GSH代谢功能影响的证据，需要进行动力学研究才能澄清。拟议的研究包括稳定的同位素动力学程序和代谢物谱分析，以确定边际维生素B6缺乏对健康男性和女性甘氨酸、丝氨酸和1C代谢以及半胱氨酸/谷胱甘肽代谢的功能影响。这些研究将扩大我们对维生素B6不足的功能影响的理解，并将产生关于人类1C代谢的营养依赖性的新信息。

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.