STRUCTURAL INVESTIGATIONS OF BIOLOGICAL NITRILE REDUCTION AND A NEW ANTI-FOLATE

生物腈还原和新型抗叶酸剂的结构研究

• 批准号: 8362425
• 负责人: MANAL A SWAIRJO
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362425
• 关键词: Active Sites; Anabolism; Antibiotics; Bacteria; Biological; Biology; Complex; Development; Engineering; Enzymes; Folate; Folate Biosynthesis Pathway; Funding; Future; GTP Cyclohydrolase; Grant; Health; Infection; Investigation; Methods; Molecular Target; National Center for Research Resources; Nitriles; Nucleoside Q; Nucleosides; Oxidoreductase; Principal Investigator; Radiation; Research; Research Infrastructure; Resistance; Resources; Source; Structure; Transfer RNA; United States National Institutes of Health; base; cost; design; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; mutant; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Current agro-industrial methods for nitrile reduction are non-specific and produce environmentally hazardous by-products. An environmentally friendly alternative is being developed: natural biocatalysis by the only nitrile reductase known in biology, QueF, an oxidoreductase recently identified in the biosynthesis of the tRNA modified nucleoside queuosine. QueF active site mutants will be crystallographically studied to uncover the enzymatic mechanism and enable future engineering of mutant enzymes that biocatalyze nitrile reduction on industrial substrates. The rise of resistant infections such as MRSA and gonnorrhoeae is a health threat worldwide, warranting the need for the development of new molecular targets for antibiotics. One such target is the new bacteria-specific GTP cyclohydrolase IB (GCYH-IB), an essential enzyme in the clinically-established folate biosynthesis pathway. SSRL facilities will be used to conduct x-ray structural analysis of GCYH-IB complexed with inhibitors to enable structure-based design of new antibiotics.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 当前用于硝酸盐还原的农业工业方法是非特异性的，并且会产生环境危险的副产品。正在开发一种环保的替代方法：生物学中已知的唯一硝酸还原酶，Quef，这是一种在TRNA修饰的核苷Queuosine的生物合成中鉴定出的氧化还原酶。 Quef活性位点突变体将进行结晶研究，以揭示酶促机制，并使未来的突变酶进行工程化，从而可以减少硝酸氮对工业底物的降低。 MRSA和Gonnorrhoeae等抗性感染的兴起是全世界的健康威胁，因此需要开发用于抗生素的新分子靶标。这样的靶标是新的细菌特异性GTP环氢酶IB（GCYH-IB），这是临床建立的叶酸生物合成途径中的必不可少的酶。 SSRL设施将用于对与抑制剂复合的GCYH-IB进行X射线结构分析，以实现基于结构的新抗生素设计。