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: 10581314
• 负责人: Thomas M Makris
• 金额: $ 19.26万
• 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/10581314
• 关键词: Affect; Anabolism; Antibiotics; Biochemical; Biochemical Reaction; Carbon; Chemistry; Critical Pathways; Dioxygen; Enzymes; Folic Acid; Generations; Genetic; Halogens; Histidine; Iron; Kinetics; Molecular; Natural Products; Pathogenicity; Pathway interactions; Proteins; Role; Site; Structure; Work; carboxylate; chemical reaction; cofactor; microbial; pathogenic bacteria; pharmacophore; programs; scaffold; tool

PROJECT SUMMARY 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.

项目摘要 双核铁酶（DIS）利用羧酸盐和组氨酸协调的辅因子到 影响合成具有挑战性的生化反应。公认的DIS角色 最近扩展到包括几种重要的天然产物生物合成途径， 包括致病细菌中叶酸的产生，抗生素的调节 通过卤素安装的效力，并合成必需的次级代谢物 通过碳 - 碳键的分裂。了解分子基础 类似的辅助因子和结构核可以执行如此多样化的功能，我们建议 研究三个新发现的DIS，其中包含几乎相同的协调图案和 总体结构脚手架，但以根本上不同的方式编排化学反应 彼此之间，并从研究充分的dis中进行氧合 基材。拟议的工作将利用一系列光谱，动力学和遗传 识别蛋白质，底物和辅因子的关键位点的工具，使这种不同 活动。阐明DI功能重编程的结构基础将 提供了一个生化模板，用于合成新的药算术和 对于微生物增殖和致病性至关重要的途径的分子基础。

项目成果

Self-sacrificial tyrosine cleavage by an Fe:Mn oxygenase for the biosynthesis of para-aminobenzoate in Chlamydia trachomatis.

• DOI: 10.1073/pnas.2210908119
• 发表时间: 2022-09-27
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Dimer-assisted mechanism of (un)saturated fatty acid decarboxylation for alkene production.

• DOI: 10.1073/pnas.2221483120
• 发表时间: 2023-05-30
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Rade, Leticia L.;Generoso, Wesley C.;Das, Suman;Souza, Amanda S.;Silveira, Rodrigo L.;Avila, Mayara C.;Vieira, Plinio S.;Miyamoto, Renan Y.;Lima, Ana B. B.;Aricetti, Juliana A.;de Melo, Ricardo R.;Milan, Natalia;Persinoti, Gabriela F.;Bonomi, Antonio M. F. L. J.;Murakami, Mario T.;Makris, Thomas M.;Zanphorlin, Leticia M.
• 通讯作者: Zanphorlin, Leticia M.

Excision of a Protein-Derived Amine for p-Aminobenzoate Assembly by the Self-Sacrificial Heterobimetallic Protein CADD.

通过自我牺牲异双金属蛋白 CADD 切除用于对氨基苯甲酸酯组装的蛋白质衍生胺。

• DOI: 10.1021/acs.biochem.3c00406
• 发表时间: 2023
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Phan,HanN;Manley,OliviaM;Skirboll,SydneyS;Cha,Lide;Hilovsky,Dalton;Chang,Wei-Chen;Thompson,PeterM;Liu,Xiaojing;Makris,ThomasM
• 通讯作者: Makris,ThomasM