STRUCTURE-FUNCTION STUDIES ON ENZYMES INVOLVED IN THE LYSINE BIOSYNTHETIC PATHWA

赖氨酸生物合成途径相关酶的结构功能研究

基本信息

批准号：
8170135
负责人：
Katherine S Bateman
金额：
$ 0.03万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8170135
关键词：
Arabidopsis Bacteria Chemicals Chlamydia Chlamydia Infections Collaborations Complex Computer Retrieval of Information on Scientific Projects Database Crystallization Crystallography Data Drug Design Enzymes Funding Genus Mycobacterium Grant Haemophilus influenzae Human Institution Investigation Lysine Lysine Biosynthesis Pathway Methods Mouse-ear Cress Pathway interactions Plants Research Research Personnel Resolution Resources Solutions Source Structure Synchrotrons Transaminases Tuberculosis United States National Institutes of Health Work antimicrobial drug beamline design epimerase high throughput screening inhibitor/antagonist mutant pathogen

Arabidopsis Bacteria Chemicals Chlamydia Chlamydia Infections Collaborations Complex Computer Retrieval of Information on Scientific Projects Database Crystallization Crystallography Data Drug Design Enzymes Funding Genus Mycobacterium Grant Haemophilus influenzae Human Institution Investigation Lysine Lysine Biosynthesis Pathway Methods Mouse-ear Cress Pathway interactions Plants Research Research Personnel Resolution Resources Solutions Source Structure Synchrotrons Transaminases Tuberculosis United States National Institutes of Health Work antimicrobial drug beamline design epimerase high throughput screening inhibitor/antagonist mutant pathogen

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项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bacterial biosynthesis of lysine forms an attractive target for the design of new antimicrobial agents because this pathway is indispensable for bacteria and is absent in humans. We have undertaken structural investigations on enzyme targets involved in the biosynthesis of lysine from bacterial pathogens and plants. Crystal structures of two of these enzymes, namely, diaminopimelate epimerase from Haemophilus influenzae and LL-diaminopimelate aminotransferase from Arabidopsis thaliana have been determined recently. Structural work is continuing on these enzymes in complex with inhibitors and of mutant forms to understand details of the catalytic mechanism for the design of effective inhibitors. Recently, we have obtained crystals of the diaminopimelate epimerase from Arabidopsis. Also, crystallization trials are currently underway on the diaminopimelate aminotransferase from the human pathogen, Chlamydia. We have an ongoing collaboration for high-throughput screening of 80,000 chemical compounds in order to find potential inhibitor leads for crystallographic analysis in our drug design efforts against Chlamydial infections. Other targets undergoing crystallization trials include diaminopimelate desuccinylase from the tuberculosis causing mycobacteria. In order to achieve the best possible resolution and quality of diffraction data, as well as for de novo structure solution using MAD/SAD methods, we require access to the synchrotron beamlines for macromolecular crystallography.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。赖氨酸的细菌生物合成形成了设计新抗菌剂的有吸引力的靶标，因为该途径对于细菌是必不可少的，并且在人类中是不可或缺的。我们已经对细菌病原体和植物赖氨酸的生物合成的酶进行了结构研究。最近已经确定了这些酶的两种酶的晶体结构，即来自拟南芥的嗜血杆菌和ll-diaminopimelate氨基转移酶的二氨基二拟酰胺表达酶。结构性工作正在与抑制剂和突变形式复杂的这些酶继续进行，以了解有效抑制剂设计的催化机制的细节。最近，我们从拟南芥中获得了二氨基二二酰化酸酯酶的晶体。此外，目前在人类病原体衣原体的二氨基二粘酸酯氨基转移酶上进行了结晶试验。在我们针对衣原体感染的药物设计工作中，我们进行了80,000种化合物的高通量筛查，以寻找晶体学分析的潜在抑制剂铅。正在进行结晶试验的其他靶标包括引起分枝杆菌的结核病中的二氨基二氨基二氨基蛋白酶。为了实现最佳的衍射数据分辨率和质量，以及使用MAD/SAD方法的从头结构解决方案，我们需要访问大分子晶体学的同步器束线。