Homeostatic Regulation of Folate Metabolism

本研究的目的是阐明铁调节叶酸代谢从而促进细胞内稳态的细胞机制。叶酸是合成核苷酸和S-腺苷蛋氨酸所必需的。这些产物是许多反应的关键代谢物，包括DNA合成、DNA甲基化、蛋白质合成和细胞信号传递。尽管这些产品对所有细胞都是必需的，但叶酸代谢在每种细胞类型中都是独特的，涉及单个碳单位的来源、叶酸输入的机制以及个别叶酸相关基因的调节。维生素缺乏、遗传易感性或药物治疗导致叶酸代谢紊乱，导致血清同型半胱氨酸升高和DNA中尿嘧啶含量增加；这些情况会导致组织和细胞特有的病理。虽然我们对与叶酸代谢相关的个体生物合成反应了解很多，但对调节叶酸代谢从而影响细胞过程的机制却知之甚少。在这项建议中，铁代谢调节叶酸代谢的生化机制将被阐明。我们提供的证据表明，丝氨酸羟甲基转移酶(CSHMT)通过铁代谢显示出强大的营养调节能力，并在调节DUMP和同型半胱氨酸的甲基化中发挥关键作用。需要检验的主要假设是：(1)。CSHMT的表达显示了铁代谢对营养的强大调节。(2)。细胞铁通过改变cSHMT的表达来调节叶酸代谢。(3)。CSHMT表达的改变影响了人MCF-7细胞中许多基因的表达。该项目的长期目标是：(1)。明确细胞用于调节叶酸代谢的动态平衡机制。(2)。阐明cSHMT的表达在叶酸代谢的动态平衡调控中的作用(S)。

The goal of this research is to elucidate the cellular mechanisms whereby iron regulates folate metabolism and thereby facilitates cellular homeostasis. Folate is necessary for the synthesis of nucleotides and s-adenosylmethionine. These products are key metabolites for numerous reactions including DNA synthesis, DNA methylation, protein synthesis, and cell signaling. Although these products are required for all cells, folate metabolism is uniquely tailored in each cell type with respect to the source of single carbon units, the mechanisms of folate import, and the regulation of individual folate-related genes. Disruption of folate metabolism by vitamin deficiency, genetic predisposition or medical therapies leads to elevated serum homocysteine and increased uracil content in DNA; conditions that lead to tissue- and cell-specific pathologies. While we understand much about the individual biosynthetic reactions associated with folate metabolism, less characterized are the mechanisms that regulate folate metabolism, and thereby influence cellular processes. In this proposal, the biochemical mechanisms whereby iron metabolism regulates folate metabolism will be elucidated. We provide evidence that the enzyme serine hydroxymethyltransferase (cSHMT) displays robust nutrient regulation by iron metabolism and plays a key role in regulating the methylation of dUMP and homocysteine. The principle hypotheses to be tested are that: (1). cSHMT expression displays robust nutrient regulation by iron metabolism. (2). cellular iron regulates folate metabolism by altering cSHMT expression. (3). changes in cSHMT expression influence the expression of many genes in human MCF-7 cells. The long-term goals of this project are: (1). to define homeostatic mechanisms used by cells to regulate folate metabolism. (2). to elucidate the role(s) of cSHMT expression in the homeostatic control of folate metabolism.