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）：适当的维生素B6状态对于健康至关重要，其辅酶形式（吡啶还源性磷酸盐，PLP）对于几种单碳（1C）代谢的几种酶（包括丝甲基羟基甲基转移酶（SHMT），甘氨酸裂解系统（GCS）（gcs），cysathione（Cysath），CyStath，Cystath，Cystath，Cystath，Cystation（Cys），至关重要。 Cystathione-Y-裂解酶（CGL）。同型半胱氨酸（HEY）是1C代谢中的核心成分，这些代谢受到BG依赖性调节，这是通过Re甲基化和转硫过程的PLP依赖性。但是，维生素B6缺乏症的血浆嘿浓度几乎没有变化。轻度的高型半胱氨酸血症和低B6状态是心血管疾病和中风的每个危险因素，归因于B6缺乏症的风险与等离子体嘿无关。在我们最近的研究中，人类的轻度至中度B6缺乏导致淋巴细胞SHMT活性降低40％，这是产生1C单元的关键酶。然而，示踪剂动力学表明禁食全身hey二甲基化没有损害，包括通过SHMT衍生自丝氨酸的1C单元的B6依赖性再甲基化。血浆甘氨酸的增加表明，低B6状态在功能上扰动1C代谢，这可能是因为低B6状态导致SHMT和GC的活性降低。血浆膀胱硫氨酸的增加表明由于CGL活性降低而导致的转移受损。大鼠研究表明，在轻度的B6缺乏症中，SHMT和CGL但没有CBS的活性也降低了。由于我们先前的输注是没有饮食氨基酸来源的，因此经硫化和其他1C反应的速率最小，这排除了对B6状态对转硫的任何影响的观察。静态测量还表明，B6缺乏导致血浆半胱氨酸的降低较小，在人体受试者中血浆谷胱甘肽（GSH）浓度增加了38％。这些发现是边际B6缺乏对半胱氨酸/GSH代谢的功能作用的证据，需要动力学研究才能澄清。拟议的研究涉及稳定的同位素动力学程序和代谢物谱分析，以确定边缘维生素B6缺乏症对甘氨酸，丝氨酸和1C代谢的功能影响，以及对健康男性和女性的半胱氨酸/GSH代谢。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1C代谢的营养依赖性的新信息。