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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

基本信息

批准号：
10636781
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
项目类别：
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

项目摘要

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，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。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temperature-dependent hydrogen deuterium exchange shows impact of analog binding on adenosine deaminase flexibility but not embedded thermal networks.

DOI：
10.1016/j.jbc.2022.102350
发表时间：
2022-09
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Gao, Shuaihua;Zhang, Wenju;Barrow, Samuel L.;Iavarone, Anthony T.;Klinman, Judith P.
通讯作者：
Klinman, Judith P.

Understanding Biological Hydrogen Transfer Through the Lens of Temperature Dependent Kinetic Isotope Effects.

DOI：
10.1021/acs.accounts.8b00226
发表时间：
2018-09-18
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Klinman JP;Offenbacher AR
通讯作者：
Offenbacher AR

Methods for Expression, Purification, and Characterization of PqqE, a Radical SAM Enzyme in the PQQ Biosynthetic Pathway.

DOI：
10.1016/bs.mie.2018.04.002
发表时间：
2018
期刊：
Methods in enzymology
影响因子：
0
作者：
Zhu W;Martins AM;Klinman JP
通讯作者：
Klinman JP

Temporal and spatial resolution of distal protein motions that activate hydrogen tunneling in soybean lipoxygenase.

远端蛋白质运动的时间和空间分辨率激活大豆脂氧酶中的氢隧穿。

DOI：
10.1073/pnas.2211630120
发表时间：
2023-03-07
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Zaragoza, Jan Paulo T.;Offenbacher, Adam R.;Hu, Shenshen;Gee, Christine L.;Firestein, Zachary M.;Minnetian, Natalie;Deng, Zhenyu;Fan, Flora;Iavarone, Anthony T.;Klinman, Judith P.
通讯作者：
Klinman, Judith P.

Hydrogen-Deuterium Exchange within Adenosine Deaminase, a TIM Barrel Hydrolase, Identifies Networks for Thermal Activation of Catalysis.