Looking in New Directions for Origins and Cryptic Mechanisms of Enzyme Catalysis

寻找酶催化起源和神秘机制的新方向

• 批准号: 10379311
• 负责人: JUDITH P KLINMAN
• 金额: $ 69.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379311
• 关键词: Active Sites; Address; Antibiotics; Area; Biochemical; Biological; Catalysis; Chemistry; Coupling; Development; Drug Targeting; Enzymes; Event; Family; Hand; Human; Hydrogen; Knowledge; Methodology; Motion; PQQ Cofactor; Pathway interactions; Peptides; Post-Translational Protein Processing; Property; Proteins; Reaction; Ribosomes; Vitamins; catalyst; cofactor; design; enzyme activity; enzyme mechanism; enzyme structure; novel; novel strategies; protein function; prototype; temporal measurement

Project Summary: This project is focused on understanding the physical and mechanistic properties of enzymes that underlie their exquisite function. In recent years, protein motions have been implicated as essential to achieve an extremely rapid catalysis of bond cleavage events at enzyme active sites. Methodology for the spatial and temporal resolution of such protein motions has been developed using enzyme prototypes that catalyze hydrogen and methyl transfer reactions. These studies are now being extended to the TIM barrel family of enzymes that represent 10% of known enzyme structures and catalyze 5 out of 7 known EC classes. With this knowledge in hand, new approaches arise for protein redesign, de novo design and drug targeting. A second emerging area in biological catalysis concerns the post-translational modification of peptides that have been synthesized at the ribosome. A combination of structural and biochemical probes is addressing the enigmatic pathway that produces the bacterial cofactor and vitamin, pyrroloquinoline quinone. As the result of a number of recent breakthrough observations, each of the catalysts within the pathway is now amenable for detailed mechanistic study. These enzymes have little or no precedence in humans, making the PQQ pathway a possible new target for antibiotic development.

项目概要： 该项目的重点是了解酶的物理和机械特性 他们精湛的功能。近年来，蛋白质运动被认为对于实现 在酶活性位点极快速地催化键断裂事件。空间和方法论 这种蛋白质运动的时间分辨率是使用催化酶原型开发的 氢和甲基转移反应。这些研究现已扩展到 TIM 桶系列 代表 10% 已知酶结构的酶，可催化 7 种已知 EC 类别中的 5 种。有了这个 有了知识，蛋白质重新设计、从头设计和药物靶向的新方法就会出现。一秒钟 生物催化的新兴领域涉及肽的翻译后修饰，这些肽已被 在核糖体处合成。结构和生化探针的结合正在解决这个神秘的问题 产生细菌辅因子和维生素吡咯喹啉醌的途径。作为一个数字的结果 根据最近的突破性观察，该途径中的每种催化剂现在都可以进行详细的研究 机理研究。这些酶在人类中很少或没有优先权，使得 PQQ 途径成为 抗生素开发的可能新目标。