Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis

天然产物生物合成中羧酸桥二铁酶的分歧

• 批准号: 10283095
• 负责人: Thomas M Makris
• 金额: $ 30.17万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283095
• 关键词: Acyl Carrier Protein; Address; Affect; Alkane 1-monooxygenase; Alkenes; Anabolism; Antibiotics; Architecture; Biochemical; Biochemical Reaction; Biology; Carbon; Chemicals; Chemistry; Complex; Critical Pathways; Cytochrome P450; Cytochrome a; Decarboxylation; Dioxygen; Enzymes; Evolution; Exhibits; Fatty Acids; Folic Acid; Funding; Generations; Genetic; Geometry; Grant; Halogens; Heme; Hemerythrin; Histidine; Hydrogen; Hydroxylation; Iron; Kinetics; Laboratories; Lead; Ligands; Ligation; Link; Membrane; Metabolism; Methane hydroxylase; Molecular; Mononuclear; Natural Products; Outcome; Oxides; Oxygen; Pathogenicity; Pathway interactions; Proteins; Reaction; Role; Scaffolding Protein; Side; Site; Structure; Work; carboxylate; catalyst; chemical reaction; cofactor; desaturase; flexibility; halogenation; interest; lens; metalloenzyme; microbial; oxidation; pathogenic bacteria; pharmacophore; programs; protein structure; scaffold; tool

Dinuclear iron enzymes (DIs) utilize a carboxylate- and histidine-coordinated cofactor to affect synthetically challenging biochemical reactions. The recognized roles for DIs have recently expanded to include several important natural product biosynthetic pathways, including the generation of folate in pathogenic bacteria, the modulation of antibiotic potency via halogen installation, and the synthesis of essential secondary metabolites through carbon-carbon bond scission. To understand the molecular basis for how a very similar cofactor and structural core can perform such diverse functions, we propose to study three newly discovered DIs that contain nearly identical coordination motifs and overall structural scaffolds, but orchestrate chemistry in ways that fundamentally differ from both each other and from well-studied DIs that instead perform the oxygenation of substrates. The proposed work will utilize an array of spectroscopic, kinetic, and genetic tools to identify key sites of the protein, substrate, and cofactor that enable such disparate activities. An elucidation of the structural basis for DI functional reprogramming will provide a biochemical template for the synthesis of new pharmacophores and the molecular basis for pathways that are critical for microbial proliferation and pathogenicity.

双核铁酶（DI）利用羧酸和组氨酸配位的辅因子来影响 具有挑战性的生物化学反应。DI的公认角色最近 扩大到包括几个重要的天然产物生物合成途径，包括 在病原菌中产生叶酸，通过卤素调节抗生素效力 安装，并通过碳-碳键合成必需的次生代谢产物 断裂为了理解一个非常相似的辅因子和结构核心 可以执行如此不同的功能，我们建议研究三个新发现的DI， 几乎相同的配位基序和整体结构支架，但协调化学， 这些方法从根本上不同于彼此，也不同于经过充分研究的DI， 进行底物的氧化。拟议的工作将利用一系列光谱， 动力学和遗传学工具，以确定蛋白质，底物和辅因子的关键位点， 这些不同的活动。DI功能重编程的结构基础 将为合成新的药效团和分子生物学提供生物化学模板。 微生物增殖和致病性的关键途径的基础。