VITAMIN B6 DEPENDENCE OF ONE-CARBON METABOLISM

维生素 B6 对一碳代谢的依赖性

• 批准号: 7605488
• 负责人: JESSE F. GREGORY
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-23 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605488
• 关键词: Affect; Amino Acid Metabolism Pathway; Antioxidants; Biological; Carbon; Catabolism; Coenzymes; Computer Retrieval of Information on Scientific Projects Database; Condition; Cysteine; Dependence; Disease; Elevation; Female; Funding; Generations; Genetic; Glutathione; Glycine; Grant; Hereditary Disease; Homocysteine; Homocystine; Human; Institution; Intake; Kinetics; Link; Metabolic; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Natural regeneration; Nutritional; Nutritional status; Pathway interactions; Phase; Plasma; Proteins; Protocols documentation; Pyridoxal Phosphate; Rate; Reaction; Recycling; Research; Research Personnel; Resources; Risk; Source; Tracer; United States National Institutes of Health; Vascular Diseases; Vitamin B 6 Deficiency; Vitamin B6; Week; analytical method; design; experience; glycine cleavage system; human subject; male; nucleotide metabolism; nutrition; young adult

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Marginal vitamin B6 deficiency, which occurs commonly worldwide, leads to a cellular deficiency of the coenzyme pyridoxal phosphate (PLP). PLP is a coenzyme in several phases of one carbon (1C) metabolism, which is the array of reactions in which one carbon units are acquired and used in reactions including nucleotide synthesis, regeneration of methionine (Met) from homocysteine (Hcy), and methylation of many biological compounds. 1C metabolism is linked to the transsulfuration pathway in which Hcy undergoes PLP-dependent catabolism leading to cysteine, whose availability governs the formation of the antioxidant glutathione. Nutritional or genetic conditions that impair 1C metabolism are associated with elevation in plasma Hcy concentration and increased risk of vascular disease. It is believed that the metabolic effects of vitamin B6 deficiency will be most pronounced following protein intake when the vitamin B6-dependent pathways of amino acid metabolism experience the greatest substrate load. The human subjects protocols of this study consist of two distinct phases intended to extend our understanding of basic human 1C metabolism and the effects of marginal vitamin B6 deficiency under postprandial conditions. Phase 1 will investigate the effects of vitamin B6 nutrition on the PLP-dependent generation of 1C units by the glycine cleavage system and on the synthesis of glutathione. Phase 2 will investigate the dependence of methionine metabolism on vitamin B6 nutritional status, with particular emphasis on the recycling of Hcy to Met. Each phase of this study will involve 14 healthy, nutritionally adequate, young adults (7 male, 7 female) who will undergo metabolite profiling and kinetic analysis using intravenously infused stable isotopic tracers performed both before and after a ~4-week period of dietary vitamin B6 restriction. Subjects will be assigned to either Phase 1 or Phase 2, which will be identical in design except for the tracers and analytical methods used. We hypothesize that vitamin B6 deficiency will yield reduction in postprandial rates of homocysteine remethylation, generation of 1C units from glycine, and synthesis of glutathione. The results of this study will aid in assessing the consequences of nutritional and genetic variables affecting human metabolism and will further our understanding of the relationships between vitamin B6 nutrition and disease.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 世界各地普遍存在的边际维生素B6缺乏症会导致细胞内辅酶磷酸吡哆醛(PLP)的缺乏。PLP是一碳(1C)代谢的几个阶段的辅酶，是获得一个碳单位并用于核苷酸合成、同型半胱氨酸(Hcy)再生蛋氨酸(Met)和许多生物化合物甲基化的一系列反应。1C代谢与跨硫途径有关，在该途径中，Hcy经历PLP依赖的分解代谢，导致半胱氨酸，半胱氨酸的可获得性控制抗氧化剂谷胱甘肽的形成。损害1C代谢的营养或遗传条件与血浆Hcy浓度升高和血管疾病风险增加有关。人们认为，当依赖维生素B6的氨基酸代谢途径经历最大底物负荷时，维生素B6缺乏对代谢的影响将在蛋白质摄入后最为明显。这项研究的人类受试者方案包括两个不同的阶段，旨在扩大我们对基本的人类1C代谢和餐后条件下边际维生素B6缺乏的影响的理解。第一阶段将研究维生素B6营养对依赖PLP的甘氨酸裂解系统产生1C单位的影响以及对谷胱甘肽合成的影响。第二阶段将研究蛋氨酸代谢对维生素B6营养状态的依赖，特别强调同型半胱氨酸到蛋氨酸的循环。这项研究的每个阶段将包括14名健康的、营养充足的年轻人(7名男性，7名女性)，他们将接受代谢物分析和动力学分析，使用静脉输注的稳定同位素示踪剂，在~4周的维生素B6限制之前和之后进行。受试者将被分配到第一阶段或第二阶段，除了使用的示踪剂和分析方法外，这两个阶段在设计上将是相同的。我们假设维生素B6缺乏会导致餐后同型半胱氨酸重新甲基化、甘氨酸生成1C单位和谷胱甘肽合成的减慢。这项研究的结果将有助于评估影响人类新陈代谢的营养和遗传变量的后果，并将进一步了解维生素B6营养与疾病之间的关系。