CHEMOTHERAPY BASED ON FOLYLPOLYGLUTAMATE SYNTHETASE

说明：本项目提出的研究结构，详细 功能和意义的酶叶酰聚谷氨酸合成酶， 用叶酸抗代谢物对人类肿瘤进行化疗。 研究 需要结合生物化学、分子和结构 旨在了解酶如何将叶酸单谷氨酸盐 依次为寡聚谷氨酸和多聚谷氨酸。 活性部位的形状 以及疏水性和带电残基的分布 活动现场。 反应的生物有机化学将是 研究使用重组人酶和一系列的探针， 活性部位 这种酶与其他酶的结构差异 在某些组织中的表达将被确定， 负责控制这些mRNA表达的机制 物种 一个收敛的一系列技术将适用于从表达 重组酶和活性位点生化研究， 从转录分析到基于结构的药物设计。

DESCRIPTION: This project proposes the study of the structure, detailed function, and significance of the enzyme folylpolyglutamate synthetase to the chemotherapy of human tumors with folate antimetabolites. The research to be pursued entails a combination of biochemical, molecular and structural studies aimed at understanding how the enzyme converts folylmonoglutamates successively to oligo and polyglutamates. The shape of the active site will be examined and the distribution of hydrophobic and charged residues within the active site. The bioorganic chemistry of the reaction will be investigated using recombinant human enzyme and a series of probes of the active site. The structural differences apparent between the enzyme expressed in some tissues will be determined as will the molecular mechanisms responsible for control of expression of the mRNA for these species. A convergent series of techniques will be applied from expression of recombinant enzymes and active site biochemical studies to transcriptional analysis to structure-based drug design.