REGULATION OF FOLATE METABOLISM

描述：（逐字来自申请人的摘要）：一个碳单元结合到 四氢叶酸用于嘌呤的从头生物合成， 胸苷酸和用于提供用于生物活性的甲基 涉及腺苷甲硫氨酸作为甲基供体的甲基化反应。的 本研究的长期目标是研究催化机制 使用四氢叶酸衍生物作为辅因子的酶，并研究 一碳代谢的调节。因为一个碳的可用性 单位是限制细胞生长速率的因素之一，这些 研究与以下化学治疗抑制剂的设计有关： 叶酸依赖酶它们也关系到我们对 控制血浆同型半胱氨酸水平的因素， 心血管疾病的发展因素。拟议的研究 关注三种叶酸依赖酶：人亚甲基四氢叶酸 还原酶（MTHFR），催化亚甲基四氢叶酸的还原 在反应中转化为甲基四氢叶酸， 提供甲基用于腺苷甲硫氨酸依赖性甲基化，和 钴胺素依赖性和钴胺素非依赖性蛋氨酸脱氢酶， 大肠埃希菌甲基转移酶催化甲基从 甲基四氢叶酸转化为高半胱氨酸，以产生四氢叶酸， 蛋氨酸。基于对E.大肠杆菌，一个模型已经被 其中酶活性由叶酸的可用性调节 衍生品;将测试该模型对监管的适用性 人类的MTHFR。钴胺素依赖的催化机理研究 和来自大肠杆菌的钴胺素非依赖性甲硫氨酸脱氢酶也是 提出了这些研究将集中在激活的机制， 底物，甲基四氢叶酸，用于转移甲基，并在 这两种酶中必需的锌离子的催化作用，将采用 各种各样的动力学、光谱和立体化学技术。

DESCRIPTION: (Verbatim from the Applicant's Abstract):One carbon units bound to tetrahydrofolate are utilized for the de novo biosynthesis of purines and thymidylate and for the provision of methyl groups for the biological methylation reactions that involve adenosylmethionine as the methyl donor. The long term goals of this research are to study the catalytic mechanisms of enzymes that use tetrahydrofolate derivatives as cofactors, and to study the regulation of one carbon metabolism. Because the availability of one carbon units is one of the factors that limits the rate of growth of cells, these studies are relevant to the design of chemotherapeutic inhibitors of folate-dependent enzymes. They are also relevant to our understanding of the factors that control the level of plasma homocysteine, an independent risk factor for the development of cardiovascular disease. The proposed studies focus on three folate-dependent enzymes: human methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate in a reaction which commits one-carbon units to provision of methyl groups for adenosylmethionine-dependent methylations, and cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli. Methionine synthases catalyze methyl transfer from methyltetrahydrofolate to homocysteine, to produce tetrahydrofolate and methionine. Based on research with MTHFR from E. coli, a model has been developed in which enzyme activity is regulated by the availability of folate derivatives; this model will be tested for its applicability to the regulation of the human MTHFR. Studies of the catalytic mechanisms of cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli are also proposed. These studies will focus on the mechanism of activation of the substrate, methyltetrahydrofolate, for transfer of the methyl group and on the catalytic role of the essential zinc ions in these two enzymes, and will employ a wide variety of kinetic, spectroscopic, and stereochemical techniques.