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Studies of metal-containing and metal-less EutT adenosyltransferases

含金属和无金属EutT腺苷基转移酶的研究

基本信息

批准号：
10058537
负责人：
Flavia Gisela Costa
金额：
$ 4.24万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2020-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058537
关键词：
Acetaldehyde Acetyl Coenzyme A Address Anabolism Animals Area Biochemical Biochemistry Biological Biophysics Catabolism Catalysis Cell physiology Cells Cellular biology Chemistry Coenzyme A Coenzymes Collaborations Complex Complex Analysis Corrinoids Crystallography Development Environment Enzymatic Biochemistry Enzymes Ethanolamine Ammonia-Lyase Ethanolamines Eukaryota Family Future Genetic Goals Health Homologous Gene Human Intestines Knowledge Laboratories Life Listeria monocytogenes Location Mediating Metabolic Metabolic Pathway Metabolism Metalloproteins Metals Microscopy Modification Molecular Molecular Biology Multiprotein Complexes Nature Pathway interactions Physiological Physiology Process Productivity Prokaryotic Cells Proteins Reaction Respiration Role Salmonella enterica Source Spectrum Analysis Sterol O-Acyltransferase Structure Substrate Specificity Techniques Training Vitamin B 12 Vitamins Work antimicrobial biophysical analysis cobamamide fitness human pathogen improved in vivo insight interdisciplinary approach interest microorganism pathogen protein protein interaction small molecule structural biology three dimensional structure

项目摘要

Project Summary/Abstract Understanding the physiological context of the metabolic needs of a pathogen provides a framework for targeted development of antimicrobials. In the case of Salmonella enterica, respiration of ethanolamine in the intestinal environment provides a fitness advantage over commensal microorganisms. Ethanolamine catabolism is a coenzyme B12-dependent pathway that occurs inside a proteinaceous compartment called the ethanolamine (Eut) metabolosome. Ethanolamine is deaminated by ethanolamine ammonia lyase (EAL) to form acetaldehyde, which eventually enters central metabolism as acetyl-CoA. EutA reactivates inactive EAL by removing dysfunctional coenzyme B12 at the expense of ATP. These reactions are needed to trigger the initial step of ethanolamine catabolism hence understanding the interactions required for these processes in the context of the Eut metabolosome would provide opportunities for targeted disruption of the metabolic pathway. There are several gaps of knowledge that need to be filled in so we can improve our understanding f ethanolamine catabolism in this human pathogen. First, the mechanism of catalysis of the adenosyltransferase EutT enzyme that converts vitamin B12 to coenzyme B12 is unknown, thus will be investigated. While the S. enterica EutT is a metalloprotein, EutT homologues in some other pathogens (e.g., Listeria monocytogenes, Clostridum tetani) function without a metal. Metal containing and metal-less Eut enzyme will be studied, and their mechanisms of catalysis compared to elucidate the role of the metal center. Second, it is not understood how coenzyme B12 is delivered to EAL from EutT. Preliminary evidence strongly suggests that EutA mediates the delivery, and that EutT, EutA and EAL may form a complex. A multidisciplinary approach (crystallography, spectroscopy, molecular biology, biochemistry, in vivo genetics, and physiology) will be used to address this complex problem. Collectively, this work will advance our understanding of how cells synthesize and deliver essential coenzymes to the enzymes that use them, in this case inside a cellular compartment.

项目总结/文摘