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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 目前用于减少腈的农业工业方法是非特异性的，并且产生对环境有害的副产物。一种环境友好的替代方法正在开发中：通过生物学中唯一已知的腈还原酶QueF进行天然生物催化，QueF是最近在tRNA修饰的核苷肌苷的生物合成中鉴定的氧化还原酶。QueF活性位点突变体将进行晶体学研究，以揭示酶促机制，并使未来的工程突变酶，生物催化工业底物上的腈还原。耐药性感染（如MRSA和淋病）的增加是全球范围内的健康威胁，这使得开发新的抗生素分子靶点的需求变得迫切。一个这样的靶标是新的细菌特异性GTP环化水解酶IB（GCYH-IB），其是临床上建立的叶酸生物合成途径中的必需酶。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。