Vitamin B6 Effects on One-Carbon Metabolism

维生素 B6 对一碳代谢的影响

• 批准号: 7271418
• 负责人: JESSE F. GREGORY
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271418
• 关键词: Amino Acids; Blood; Carbon; Cardiovascular Diseases; Coenzymes; Cystathionine; Cysteine; Data; Dependence; Enzymes; Erythrocytes; Fasting; Generations; Glutathione; Glycine; Glycine Hydroxymethyltransferase; Goals; Health; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Impairment; Infusion procedures; Investigation; Kinetics; Lead; Lyase; Lymphocyte; Measurement; Metabolic; Metabolism; Methionine; Methods; Nutritional; Nutritional status; Plasma; Procedures; Process; Protocols documentation; Pyridoxal Phosphate; Rate; Rattus; Reaction; Regulation; Research; Research Personnel; Risk; Risk Factors; Serine; Source; Stroke; Sulfur Amino Acids; Testing; Tracer; Vitamin B 6 Deficiency; Vitamin B6; Woman; base; glycine cleavage system; human subject; in vivo; men; programs; stable isotope

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.

描述（由申请人提供）：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）对于一碳 (1C) 代谢的多种酶至关重要，包括丝氨酸羟甲基转移酶 (SHMT)、甘氨酸裂解系统(GCS)、胱硫醚 R>-合酶 (CBS) 和胱硫醚-γ-裂解酶 (CGL)。同型半胱氨酸 (Hey) 是 1C 代谢的核心成分，通过 PLP 依赖性的再甲基化和转硫过程受到 BG 依赖性调节。然而，维生素B6缺乏时血浆Hey浓度变化不大。轻度高同型半胱氨酸血症和 B6 水平低都是心血管疾病和中风的危险因素，而 B6 缺乏引起的风险与血浆 Hey 无关。在我们最近的研究中，人类轻度至中度 B6 缺乏导致淋巴细胞 SHMT 活性降低 40%，SHMT 活性是产生 1C 单位的关键酶。然而，示踪动力学表明，空腹全身 Hey 再甲基化没有受到损害，包括通过 SHMT 从丝氨酸衍生的 1C 单元的 B6 依赖性再甲基化。血浆甘氨酸增加表明低 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。血浆胱硫醚增加表明由于 CGL 活性降低而导致转硫受损。大鼠研究表明，即使是轻度 B6 缺乏，SHMT 和 CGL 的活性也会降低，但 CBS 不会降低。由于我们之前的输注是在没有膳食氨基酸来源的情况下进行的，因此转硫作用和其他 1C 反应的发生率很小，这排除了观察 B6 状态对转硫作用的任何影响。静态测量还表明，维生素 B6 缺乏会导致人类受试者血浆半胱氨酸小幅下降，血浆谷胱甘肽 (GSH) 浓度增加 38%。这些发现证明了边缘 B6 缺乏对半胱氨酸/谷胱甘肽代谢的功能影响，需要进行动力学研究来澄清。拟议的研究涉及稳定同位素动力学程序和代谢物谱分析，以确定边缘维生素 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/GSH 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，并将产生有关人类 1C 代谢的营养依赖性的新信息。