VITAMIN B6 DEPENDENCE OF ONE-CARBON METABOLISM

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。 维生素B6缺乏导致辅酶磷酸吡哆醛-PLP的细胞缺乏。PLP是一个碳-1C代谢阶段的辅酶--一个碳单位用于核苷酸合成、同型半胱氨酸-同型半胱氨酸再生蛋氨酸-蛋氨酸以及许多生物化合物的甲基化等反应。1C代谢与同型半胱氨酸依赖PLP分解代谢产生半胱氨酸的跨硫代谢途径有关。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。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。每一阶段将涉及14名年轻人，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，在限制饮食维生素B6前后进行，为期约4周。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。

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. Vitamin B6 deficiency leads to a cellular deficiency of the coenzyme pyridoxal phosphate-PLP. PLP is a coenzyme in phases of one carbon-1C metabolism - the array in which one carbon units are 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. 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. 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. Each phase will involve 14 young adults, who will undergo metabolite profiling and kinetic analysis using intravenously infused stable isotopic tracers performed 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.