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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：人铁（II） - 和2-（氧）谷氨酸酯依赖性（Fe/2og）二氧酶催化对中心生命过程至关重要的反应中灭活的脂肪族碳中心的羟基化（例如，代谢及其代谢及其转疗法，均等遗传性，并具有多种遗传性，并具有多种含量。植物，真菌和细菌使Fe/2og结构和功能平台多样化，使用它来使脂肪碳中心的卤素化，脱氢，环化和立体变速器进行迷惑阵列。由于产生大量重要自然产物药物的生物合成机制被这种Fe/2og氧酶取代，因此对反应机制的预测理解以及单个酶如何指导它们可以使酶和途径重新使用量身定制的药物化合物。 Having recently made great progress towards understanding the hydroxylation, halogenation, and stereoinversion outcomes, we turn in this project to two of the least well-understand 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抗生素克拉氏酸和萘章霉素，麻醉孢子胺和杀虫剂，氯洛林。我们将阐明催化这些神秘反应的酶的结构和机制，以发展对这一重要酶家族化学的综合理解。