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: 10304210
• 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/10304210
• 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（DIs）利用羧酸和组氨酸协调的辅因子来影响