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: 9139962
• 负责人: JOSEPH M BOLLINGER
• 金额: $ 43.57万
• 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/9139962
• 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; 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; Health; Homology Modeling; Human; Hydrogen; Hydroxylation; Individual; Insecticides; Iron; Kinetics; Label; Lactamase; Life; Ligands; Measurement; Mediating; Metabolism; Mixed Function Oxygenases; Monitor; Mutagenesis; Natural Product Drug; Natural Products; Outcome; Oxygenases; Pathway interactions; Positioning Attribute; Process; Publishing; Reaction; Resolution; Scheme; Scopolamine; Site; Soil; Structure; Succinates; Transcriptional Regulation; Tropanes; Uncertainty; Work; abstracting; analog; cofactor; dehydrogenation; enzyme mechanism; enzyme pathway; enzyme substrate complex; halogenation; hydroxyl group; improved; inhibitor/antagonist; member; novel therapeutics; oxidation; plant fungi; 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/2 OG）双加氧酶在对中心生命过程（例如，代谢及其调节、转录、表观遗传）并且与若干疾病相关。植物、真菌和细菌已经使Fe/2 OG结构和功能平台多样化，使用它进行一系列令人困惑的氧化转化，包括脂肪族碳中心的卤化、还原、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这种Fe/2 OG加氧酶，因此对反应机制以及单个酶如何指导它们的预测性理解可以使酶和途径的重新用途化，以定制药物化合物。最近在理解羟基化、卤化和立体转化结果方面取得了很大进展，我们在该项目中转向由该酶家族成员介导的两种最不了解的反应类型：草酰环加成1，3-和1，5-脱氢（氧杂环化）和烯烃安装1，2-脱氢抗生素克拉维酸和萘多霉素、麻醉剂东莨菪碱和杀虫剂诺洛林的途径上的（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，以全面了解这个重要酶家族的化学性质。