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.

项目总结/摘要 所有的生物体都能通过酶的作用获得脱氧核苷酸作为DNA合成和修复的底物 称为核糖核苷酸还原酶（RNR）。几种已知类型的RNR，已被分为 I类、II类和III类的不同之处在于它们用来引发它们的过渡金属和自由基化学反应。 常见的具有挑战性的还原/脱羟基反应。最近的研究表明， 使用与人类I类a亚类显著不同的I类RNR感染人类并引起疾病 酵素这些微生物RNR中的一些（亚类B和d）在所述微生物RNR中使用锰而不是铁。 被认为是对人体免疫反应引起的缺铁的一种适应，而其他人则两者兼而有之。 金属（c类）。我们刚刚发现一种新型的RNR来自链球菌性咽喉炎的病原体， 猩红热可能完全逃脱了通常对过渡金属的依赖， 未知类型的稳定氨基酸基团，从而建立e亚类。这个项目将揭示如何准确地 I类RNR的三个新子类（包括d和e）的成员，最近在 病原菌获得它们的催化活性并启动核苷酸还原。非常不同的启蒙 病原体的酶所使用的化学物质为抗生素选择性抑制它们提供了机会。这 该项目将为此类药物发现工作提供概念基础，并揭示如何 病原微生物已经适应科普宿主的敌对免疫反应。