Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments

多种过渡金属和自由基化学使细菌在限制性环境中生产 2-脱氧核糖核苷酸

• 批准号: 10165753
• 负责人: JOSEPH M BOLLINGER
• 金额: $ 37.74万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165753
• 关键词: Active Sites; Aerococcus; Amino Acids; Ammonium; Antibiotics; Bacteria; Catalysis; Catalytic Domain; Cations; Cells; Charge; Chemistry; Complex; Cysteine; DNA; DNA Repair; DNA biosynthesis; Data; Deoxyribonucleotides; Dependence; Disease; Electrons; Ensure; Environment; Enzymes; Evolution; Failure; Flavobacteria; Flavoproteins; Free Radicals; Gene Expression Profiling; Generations; Genes; Growth; Hospitals; Human; Hydrophobicity; Immune response; In Vitro; Infection; Iron; Ligands; Light; Lysine; Manganese; Metals; Nucleotides; Organism; Oxidants; Oxides; Pharyngeal structure; Physiological; Positioning Attribute; Process; Production; Property; Proteins; Reaction; Reporting; Ribonucleotide Reductase; Role; Scarlet Fever; Site; Streptococcus pyogenes; Structure; Superoxides; System; Tissues; Transition Elements; Work; X-Ray Crystallography; base; cofactor; complex IV; dehydroxylation; deprivation; design; drug discovery; in vivo; member; microbial; opportunistic pathogen; oxidation; pathogen; pathogenic bacteria; pathogenic microbe

Project Summary/Abstract All organisms obtain the deoxynucleotide substrates for DNA synthesis and repair by the action of an enzyme known as ribonucleotide reductase (RNR). The several known types of RNRs, which have been divided into classes I, II, and III, differ in the transition-metal and free-radical chemistry that they use to initiate their common, challenging reduction/dehydroxylation reaction. Recent studies have shown that many bacteria that infect and cause disease in humans use class I RNRs that differ markedly from the human class I, subclass a enzyme. Some of these microbial RNRs (subclasses b and d) use manganese instead of iron in what is thought to be an adaptation to iron deprivation caused by the human immune response, and others use both metals (subclass c). We just discovered that a new type of RNR from the causative agent of strep throat and scarlet fever may have fully escaped the usual dependence on transition metals by using a previously unknown type of stable amino acid radical, thus founding subclass e. This project will reveal precisely how the members of three new subclasses of class I RNRs (including d and e) that were recently identified in pathogenic bacteria acquire their catalytic activity and initiate nucleotide reduction. The very different initiation chemistry used by the pathogens' enzymes offers opportunities for their selective inhibition by antibiotics. This project will provide the conceptual underpinnings for such drug discovery efforts and will shed light on the ways in which pathogenic microbes have adapted to cope with their hosts' hostile immune response.

项目摘要/摘要 所有生物都会通过酶的作用获得脱氧核苷酸底物进行DNA合成和修复 称为核糖核苷酸还原酶（RNR）。已知的几种已知类型的RNR，已分为 I类，II和III类在过渡金属和自由基化学方面有所不同 常见的，具有挑战性的还原/脱氢反应。最近的研究表明，许多细菌 感染并引起人类疾病使用与人类I类明显不同的I类RNR，子类A 酶。这些微生物RNR中的一些（子类B和D）使用锰代替铁。 被认为是由人类免疫反应引起的铁剥夺的一种适应，而其他人则使用 金属（子类C）。我们刚刚发现，从链球菌喉咙的病因和 猩红热可能通过使用先前的 稳定氨基酸自由基的未知类型，因此建立了亚类E。该项目将准确揭示 最近在 致病细菌获得其催化活性并启动核苷酸还原。截然不同的启动 病原体使用的化学性质为抗生素的选择性抑制提供了机会。这 项目将为这种药物发现工作提供概念上的基础，并将阐明方式 在其中，致病性微生物已适应应对其宿主的敌对免疫反应。