Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases

安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制

• 批准号: 8965103
• 负责人: JOSEPH M BOLLINGER
• 金额: $ 46.12万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965103
• 关键词: Active Sites; Alcohols; Aldehydes; Alkaloids; Alkenes; Amines; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Anabolism; Anesthetics; Anti-Bacterial Agents; Antibiotics; Arginine; Bacteria; Biochemical Pathway; Biological Factors; Carbon; Chemicals; Chemistry; Clavulanic Acids; Complement component C4a; Complex; Coupled; Couples; Coupling; Cyclization; Data; Deuterium; Dioxygenases; Disease; Drug Compounding; Drug Design; Enzymes; Epigenetic Process; Epoxy Compounds; Ethylene Oxide; Family; Glutamates; Glutarates; Guanidines; Homology Modeling; Human; Hydrogen; Hydroxylation; Individual; Insecticides; Iron; Kinetics; Label; Lactamase; Life; Ligands; Measurement; Mediating; Metabolism; Mixed Function Oxygenases; Monitor; Mutagenesis; Natural Product Drug; Outcome; Oxygenases; Pathway interactions; Positioning Attribute; Process; Publishing; Reaction; Resolution; Scheme; Scopolamine; Site; Soil; Solutions; Structure; Succinates; Transcriptional Regulation; Tropanes; Uncertainty; Work; abstracting; analog; clavaminate synthase; cofactor; dehydrogenation; enzyme mechanism; enzyme pathway; enzyme substrate complex; halogenation; hydroxyl group; improved; inhibitor/antagonist; member; oxidation; plant fungi; public health relevance; research study

 DESCRIPTION (provided by applicant): Human iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) dioxygenases catalyze hydroxylation of inactivated aliphatic carbon centers in reactions that are fundamentally important to central life processes (e.g., metabolism and its regulation, transcription, epigenetic inheritance) and relevant to several diseases. Plant, fungi, and bacteria have diversified the Fe/2OG structural and functional platform, using it for a bewildering array of oxidative transformations that include halogenations, dehydrogenations, cyclizations and stereoinversions of aliphatic carbon centers. As the biosynthetic machinery generating a large number of important natural-product drugs are replete with such Fe/2OG oxygenases, a predictive understanding of the reaction mechanisms and how the individual enzymes direct them could enable re-purposing of the enzymes and pathways for tailor-made drug compounds. Having recently made great progress toward understanding the hydroxylation, halogenation, and stereoinversion outcomes, we turn in this project to two of the least well- understood reaction types mediated by members of this enzyme family: oxacycle-installing 1,3- and 1,5- dehydrogenation (oxacyclization) and olefin-installing 1,2-dehydrogenation (desaturation) reactions on the pathways to the antibiotics clavulanic acid and napthyridomycin, the anesthetic scopolamine, and insecticide, norloline. We will elucidate the structures and mechanisms of the enzymes catalyzing these enigmatic reactions to develop an integrated understanding of the chemistry of this important enzyme family.

 描述（由申请人提供）：人铁（II）-和2-（氧代）戊二酸依赖性（Fe/2OG）双加氧酶在对中心生命过程（例如代谢和代谢）至关重要的反应中催化失活脂肪族碳中心的羟基化。其调控、转录、表观遗传）以及与多种疾病相关的Fe/2OG结构和功能平台已多样化，并将其用于多种疾病。一系列令人眼花缭乱的氧化转化，包括脂肪族碳中心的卤化、脱氢、环化和立体转化，由于产生大量重要天然产物药物的生物合成机器充满了此类 Fe/2OG 加氧酶，因此需要对反应机制进行预测性理解。单个酶如何指导它们可以重新利用酶和途径来定制药物化合物，最近在理解酶和药物化合物方面取得了巨大进展。由于羟基化、卤化和立体反转结果，我们在这个项目中转向由该酶家族成员介导的两种最不为人所知的反应类型：氧杂环安装 1,3- 和 1,5- 脱氢（氧杂环化）和烯烃-在抗生素克拉维酸和萘霉素、麻醉剂东莨菪碱的途径上安装 1,2-脱氢（去饱和）反应，我们将阐明催化这些神秘反应的酶的结构和机制，以全面了解这一重要酶家族的化学性质。