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（DI）利用羧酸和组氨酸配位的辅因子， 影响合成挑战性的生化反应。DI的公认角色包括 最近扩展到包括几个重要的天然产物生物合成途径， 包括病原菌中叶酸的产生，抗生素的调节， 通过卤素装置的效力，以及必需的次级代谢产物的合成 通过碳-碳键断裂。为了了解一个非常重要的 相似辅因子和结构核心可以执行如此不同的功能，我们建议 研究了三个新发现的含有几乎相同配位基序的DI， 整体结构支架，但编排化学的方式， 从彼此和从充分研究的DI，而不是执行的氧化， 印刷受体.拟议的工作将利用一系列光谱，动力学和遗传学方法。 工具，以确定关键位点的蛋白质，底物，和辅因子，使这种不同的 活动DI功能重编程的结构基础的阐明将 为新药效团的合成提供了生物化学模板， 微生物增殖和致病性的关键途径的分子基础。

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