MECHANISMS OF PYRIDOXAL-5'-PHOSPHATE DEPENDENT ENZYMES

吡哆醛-5-磷酸依赖性酶的机制

基本信息

批准号：
6924455
负责人：
ROBERT STEPHEN PHILLIPS
金额：
$ 6.48万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-09-01 至 2006-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (adapted from applicant's abstract): The investigators are studying the mechanism of pyridoxal-5'-phosphate-dependent enzymes that break or form carbon-carbon bonds. These enzymes include tryptophan indole-lyase, tyrosine phenol-lyase, tryptophan synthase, bacterial and human kynureninases, and aspartate beta-decarboxylase. They are evaluating the reaction mechanism of tyrosine phenol-lyase and tryptophan indole-lyase. The investigators are determining the roles of specific amino acids in catalysis and reaction specificity by both site-directed mutagenesis and by synthesis of a C-terminal peptide containing unnatural amino acids. The investigators are probing the mechanism of the reaction of these enzymes by various kinetic techniques, including rapid scanning stopped flow spectrophotometry and rapid chemical quench. They will design, synthesize, and evaluate novel inhibitors of tryptophan indole-lyase that may be useful in the treatment of Haemophilus influenzae meningitis. The potent competitive inhibitors of kynureninase that they are designing and synthesizing, based on their studies of the bacterial enzyme, have been patented and are undergoing studies to evaluate their potential in the treatment of neurological disorders such as stroke. The investigators will determine and compare the structure and reaction mechanism of bacterial and human kynureninases as well as aspartate beta-decarboxylase. More information on the structure and mechanism of kynureninases mat lead to the design of other more selective and potent inhibitors. The central role of pyridoxal-5'phosphate-dependent enzymes in the metabolism of amino acids and amines and in the biosynthesis of important bioactive metabolites, makes them attractive targets for the design of mechanism-based inhibitors which may be useful for drugs. Thus the results of this research are likely to make a significant contribution to the goal of improving health care for Americans in the future.

描述（改编自申请人的摘要）：研究人员正在研究 5'-磷酸吡哆醛依赖性酶的分解或形成机制碳-碳键。这些酶包括色氨酸吲哚裂解酶、酪氨酸酚裂解酶、色氨酸合酶、细菌和人类犬尿氨酸酶，以及天冬氨酸β-脱羧酶。他们正在评估反应机理酪氨酸苯酚裂解酶和色氨酸吲哚裂解酶。调查人员是确定特定氨基酸在催化和反应中的作用通过定点诱变和 C 端合成实现特异性含有非天然氨基酸的肽。调查人员正在调查此事通过各种动力学技术研究这些酶的反应机制，包括快速扫描停流分光光度法和快速化学分析法淬火。他们将设计、合成和评估新型抑制剂色氨酸吲哚裂解酶可用于治疗嗜血杆菌流感脑膜炎。犬尿氨酸酶的有效竞争性抑制剂他们正在根据对细菌的研究进行设计和合成酶，已获得专利并正在进行研究以评估其治疗中风等神经系统疾病的潜力。这研究人员将确定并比较结构和反应机制细菌和人类犬尿氨酸酶以及天冬氨酸β-脱羧酶。有关犬尿氨酸酶结构和机制的更多信息其他更具选择性和更有效的抑制剂的设计。的核心作用氨基酸代谢中的吡哆醛-5'磷酸依赖性酶胺和重要生物活性代谢物的生物合成，使它们设计基于机制的抑制剂的有吸引力的目标可能是对药物有用。因此，这项研究的结果可能会产生对改善美国人医疗保健的目标做出了重大贡献未来。