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Enzymes: Structure, Mechanism, Function and Inhibition

酶：结构、机制、功能和抑制

基本信息

批准号：
8080168
负责人：
DEBRA DUNAWAY-MARIANO
金额：
$ 48.6万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-02-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080168
关键词：
Acyl Carrier Protein Acyl Coenzyme A Acyltransferase Anabolism Binding Biochemical Process Biochemistry Biodiversity Biological Biological Process Catalysis Cell Cycle Cell Survival Cell division Cell membrane Cell physiology Cells Chemicals Chimeric Proteins Coenzyme A Complex Development Energy Metabolism Enterobactin Enzymes Escherichia coli Fatty Acids Future Glycerol Goals Health Human Hydrolysis In Vitro Interdisciplinary Study Knowledge Link Lipids Location Measures Medicine Operon Oxidoreductase Participant Performance Phosphatidylserine Synthase Physiological Play Porphyromonas gingivalis Prevention Protein S Proteins Proto-Oncogene Proteins c-akt Regulation Research Role Site Solutions Specificity Structure Structure-Activity Relationship Substrate Domain System Testing Work acyl group analog base carboxylate catalyst chemical function drug discovery enzyme structure falls human disease human thioesterase in vivo insight novel novel therapeutics programs protein function response thioester

项目摘要

DESCRIPTION (provided by applicant): The structure and function of the cell membrane, as well as many aspects of energy metabolism and cell cycling, are directly dependent on acyl-CoA thioesters and their CoA and fatty acid constituents. The complex interplay between CoA, short or long chain carboxylates, and acyl-CoA thioesters (and lipid derived products) in directing the functions and responses of cells is not well understood even at the most elementary level. This research program focuses on the delineation of cellular processes in which transformations of acyl-CoA metabolites or acyl-S-proteins play important roles. The catalysts for these transformations reside mainly in the hotdog fold superfamily. An integrated approach that combines the efforts of a diverse research team will be used to characterize hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The overall goal is to gain an understanding of the relationships that exist between enzyme structures and the mechanisms of substrate recognition and catalysis in vitro and in vivo. This fundamental knowledge is required for the development of new drugs and for the discovery of new biochemical processes. An understanding of the relationship between in vitro chemical function (i.e., range of substrates and catalytic efficiencies) and the actual cellular chemical function (i.e., physiological substrates and in vivo catalytic efficiencies) will provide insight into the need for and mechanism of regulation of thioesterase activity within the cell. In addition, knowledge about relationships between structure and chemical and cellular functions should reveal how thioesterases successfully execute their evolved biological roles. PUBLIC HEALTH RELEVANCE: This project employs an integrated approach that relies on a multidisciplinary research team to define the hotdog thioesterases at the cellular, chemical, mechanistic, and structural levels. The results of this effort will facilitate the development of new therapeutic drugs and the discovery of new biochemical processes.

描述（由申请人提供）：细胞膜的结构和功能，以及能量代谢和细胞循环的许多方面，直接依赖于酰基辅酶a硫酯及其辅酶a和脂肪酸成分。辅酶a、短链或长链羧酸盐和酰基辅酶a硫酯（以及脂质衍生产物）之间的复杂相互作用在指导细胞功能和反应中的作用，即使在最基本的水平上也没有得到很好的理解。本研究项目侧重于描述酰基辅酶a代谢物或酰基s蛋白转化起重要作用的细胞过程。这些转变的催化剂主要存在于热狗褶皱超家族中。一个综合的方法，结合不同的研究团队的努力，将被用来表征热狗硫酯酶在细胞，化学，机制和结构水平。总体目标是了解酶结构与底物识别和催化机制之间存在的关系，在体外和体内。这些基础知识是开发新药和发现新的生化过程所必需的。了解体外化学功能（即底物范围和催化效率）与实际细胞化学功能（即生理底物和体内催化效率）之间的关系，将有助于深入了解细胞内硫酯酶活性调节的需求和机制。此外，关于结构与化学和细胞功能之间关系的知识应该揭示硫酯酶如何成功地执行其进化的生物学作用。公共卫生相关性：该项目采用综合方法，依靠多学科研究团队在细胞、化学、机制和结构水平上定义热狗硫酯酶。这一努力的结果将有助于开发新的治疗药物和发现新的生化过程。

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure and catalysis in the Escherichia coli hotdog-fold thioesterase paralogs YdiI and YbdB.

DOI：
10.1021/bi500334v
发表时间：
2014-07-29
期刊：
Biochemistry
影响因子：
2.9
作者：
Wu R;Latham JA;Chen D;Farelli J;Zhao H;Matthews K;Allen KN;Dunaway-Mariano D
通讯作者：
Dunaway-Mariano D

Catalytic Mechanism of the Hotdog-Fold Thioesterase PA1618 Revealed by X-ray Structure Determination of a Substrate-Bound Oxygen Ester Analogue Complex.

通过底物结合氧酯类似物复合物的 X 射线结构测定揭示热狗折叠硫酯酶 PA1618 的催化机制。

DOI：
10.1002/cbic.201700322
发表时间：
2017
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
0
作者：
Latham,JohnA;Ji,Tianyang;Matthews,Kaila;Mariano,PatrickS;Allen,KarenN;Dunaway-Mariano,Debra
通讯作者：
Dunaway-Mariano,Debra

Investigation of the regiospecificity and stereospecificity of proton transfer in the yeast inorganic pyrophosphatase catalyzed reaction.

酵母无机焦磷酸酶催化反应中质子转移的区域特异性和立体特异性的研究。