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

项目摘要： 该项目的重点是了解酶的物理和机械特性， 其精致的功能。近年来，蛋白质运动被认为是实现生物学功能的关键。 在酶活性位点处的键断裂事件的极其快速的催化。空间和 这种蛋白质运动的时间分辨已经使用催化 氢和甲基转移反应。这些研究现在正在扩展到TIM桶系列， 代表已知酶结构的10%并且催化7种已知EC类别中的5种的酶。与此 掌握了这些知识后，蛋白质重新设计、从头设计和药物靶向的新方法就出现了。第二 生物催化中的新兴领域涉及已被修饰的肽的翻译后修饰。 在核糖体上合成。结构和生化探针的组合正在解决神秘的 产生细菌辅因子和维生素吡咯喹啉醌的途径。由于一个数字 最近的突破性观察，每一个催化剂的途径，现在是适合详细 机械学研究这些酶在人类中几乎没有或没有优先权，使PQQ途径成为一种 抗生素开发的可能新目标。

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.