Mapping the structural basis for mechanistic diversity in metalloenzyme superfamilies

绘制金属酶超家族机械多样性的结构基础

• 批准号: 10598851
• 负责人: Amie K Boal
• 金额: $ 5.87万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598851
• 关键词: Amino Acids; Bacteria; Biochemical; Biological; Cells; Chemistry; Communicable Diseases; DNA biosynthesis; Doctor of Philosophy; Enzyme Inhibition; Enzymes; Goals; Mentors; Methodology; Microbiology; Nucleic Acids; Organism; Proteins; Ribonucleotide Reductase; Route; System; Testing; Therapeutic Intervention; Tyrosine; Work; biological systems; cofactor; commensal microbes; metalloenzyme; microbial; non-Native; novel; parent grant; pathogen; pathogenic microbe; training opportunity

Project Summary The parent grant for this supplement aims to discover novel enzymatic cofactors involved in DNA biosynthesis in pathogens. The overarching goal is to enable new routes to enzyme inhibition in bacteria that cause infectious disease. Here we will investigate the mechanism of assembly of an essential tyrosine-derived post-translationally modified radical cofactor found in a subclass of microbial ribonucleotide reductases through incorporation of non- native amino acids. This approach will allow us to identify aspects of cofactor assembly that could be targeted for disruption by therapeutic interventions. In a second aim, we will characterize the cofactor used by this enzyme subclass in a native host organism. The project as a whole will set the stage for understanding how this enzyme subclass is used inside the cell, ultimately allow us to test the impact of disruption of cofactor assembly in a relevant biological context. The project provides an excellent training opportunity for the Ph.D. candidate supported by the supplement in work at the interface between chemistry and microbiology. A collaborative mentoring team is in place with expertise in non-native amino acid methodology, structural and biochemical characterization of proteins, and cultivation of pathogenic and commensal microbes.

项目摘要 这种补充剂的父授予旨在发现参与DNA生物合成的新型酶促辅因子 在病原体中。总体目标是使新的途径在细菌中抑制酶，以引起感染力 疾病。在这里，我们将研究基本酪氨酸衍生后翻译的组装机制 通过融合非 - 天然氨基酸。这种方法将使我们能够确定可以针对目标的辅因子组件的各个方面 通过治疗干预措施破坏。在第二个目标中，我们将表征该酶使用的辅助因子 本地寄主生物中的子类。整个项目将为理解这种酶的方式奠定基础 子类用于细胞内部，最终使我们能够测试辅因子组件破坏的影响 相关的生物环境。该项目为博士提供了绝佳的培训机会。候选人 在化学和微生物学之间的界面上的工作中补充剂的支持。协作 指导团队在非本地氨基酸方法，结构和生化方面具有专业知识 蛋白质的表征以及致病性和共生微生物的培养。