Deciphering microbial metalloenzyme functions in microaerobic host environments

破译微生物金属酶在微氧宿主环境中的功能

• 批准号: 10711457
• 负责人: Lauren Julia Rajakovich
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711457
• 关键词: Aerobic; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Biochemical; Biochemical Reaction; Biochemistry; Bioinformatics; Biological; Biological Process; Catalysis; Cell physiology; Chemistry; Drug resistance; Environment; Enzymes; Family; Gastrointestinal tract structure; Genomics; Goals; Human; Human body; Hydroxylation; Knowledge; Lung; Microbe; Modification; Molecular; Mucous Membrane; Oxidases; Oxidation-Reduction; Oxygen; Pathogenesis; Play; Proteins; RNA; Reaction; Reactive Oxygen Species; Research; Role; Source; Therapeutic; Work; chemical function; cofactor; commensal bacteria; environmental change; gut microbes; host-microbe interactions; member; metalloenzyme; microbial; novel; novel therapeutics; pathogenic bacteria; programs; response; wound

Project Summary Commensal and pathogenic bacteria inhabit various oxygen-depleted niches in the human body, such as the gastrointestinal tract, wound tissue, and the lung mucosa. Adaptation to these environments requires distinct anaerobic biochemistry to support colonization and survival. An understanding of these biochemical strategies could present unique opportunities to develop novel therapeutics that overcome challenges of antibiotic resistance and bacterial persistence. However, we lack fundamental knowledge of the diverse chemistry that microbes use in anaerobic and microaerobic environments. The proposed studies outline our approach to elucidate the molecular mechanisms, biochemical reactions, and biological roles of metalloenzymes in host- microbe interactions. Metalloenzymes play central roles in cellular redox chemistry. Whereas classes of metalloenzymes that active oxygen for redox reactions have been studied for decades, metalloenzyme families that function in the absence of oxygen remain poorly characterized. In this project, we interrogate the chemical and biological functions of a newly discovered family of metalloenzyme oxidases that are prevalent in bacterial pathogens and human gut microbes. The few known representatives of this family catalyze oxygen-independent hydroxylation reactions in key cellular processes, including cofactor biosynthesis and RNA modification. We will use these known enzymes to establish the requirements for catalysis and to discern their postulated roles in microoxic conditions. Beyond the members with established functions, emerging metalloenzyme families also represent an untapped source of biochemical diversity. We will leverage genomics and protein bioinformatics to discover new enzymatic chemistry within this poorly characterized superfamily. The proposed work will reveal previously unknown redox chemistry, establish biochemical responses to microaerobic conditions, and set the stage to interrogate the importance of these reactions in host-microbe interactions. The ultimate goal of this research program is to gain a molecular understanding of microbial adaptation to O2 limitation that can be leveraged to treat elusive drug-resistant bacterial pathogens.

项目概要 共生菌和致病菌栖息在人体内各种缺氧的生态位中，例如 胃肠道、伤口组织和肺粘膜。适应这些环境需要不同的 厌氧生物化学以支持定植和生存。了解这些生化策略 可以提供独特的机会来开发克服抗生素挑战的新疗法 耐药性和细菌持久性。然而，我们缺乏多种化学的基础知识， 微生物在厌氧和微氧环境中的使用。拟议的研究概述了我们的方法 阐明宿主中金属酶的分子机制、生化反应和生物学作用 微生物相互作用。金属酶在细胞氧化还原化学中发挥着核心作用。而类 氧化还原反应中活性氧的金属酶已经研究了数十年，金属酶家族 这种在缺氧条件下的功能仍知之甚少。在这个项目中，我们询问了化学物质 新发现的细菌中普遍存在的金属酶氧化酶家族的生物学功能 病原体和人类肠道微生物。该家族中少数已知的代表不依赖于氧进行催化 关键细胞过程中的羟基化反应，包括辅因子生物合成和 RNA 修饰。我们将 使用这些已知的酶来确定催化的要求并辨别它们在 微氧条件。除了具有既定功能的成员之外，新兴的金属酶家族也 代表了生化多样性的未开发来源。我们将利用基因组学和蛋白质生物信息学 在这个特征不明的超家族中发现新的酶化学。拟议的工作将揭示 以前未知的氧化还原化学，建立对微氧条件的生化反应，并设定 阶段来询问这些反应在宿主-微生物相互作用中的重要性。此次活动的最终目的 研究计划是为了从分子角度了解微生物对氧气限制的适应，这可以 用于治疗难以捉摸的耐药细菌病原体。