MECHANISMS OF PYRIDOXAL-5'-PHOSPHATE DEPENDENT ENZYMES

吡哆醛-5-磷酸依赖性酶的机制

• 批准号: 6519347
• 负责人: ROBERT STEPHEN PHILLIPS
• 金额: $ 19.11万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519347
• 关键词: antibacterial agents; bacterial proteins; biochemical evolution; carbon carbon hydrolase; carbon carbon lyase; drug design /synthesis /production; enzyme activity; enzyme inhibitors; enzyme mechanism; enzyme structure; kynurenine; peptide chemical synthesis; protein sequence; pyridoxal phosphate; site directed mutagenesis; spectrometry; stop flow technique; transaminases; tryptophan; tryptophan synthase; tyrosine

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（改编自申请人摘要）：研究人员正在研究