Three-membered Ring Metabolites, Inhibition and Formation

三元环代谢物、抑制和形成

基本信息

批准号：
7907114
负责人：
HUNG-WEN LIU
金额：
$ 25.89万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7907114
关键词：
Address Alcohols Alkenes Anabolism Attention Aziridines Binding Biochemical Biological Biological Factors Biology Catalysis Cations Chemicals Chemistry Cobalamin Coenzymes Cyclopropanes Development Drug Design Electron Nuclear Double Resonance Elements Engineering Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Ethylene Oxide Family Fosfomycin Funding Future Gene Cluster Goals Grant Health Heme Iron Human Investigation Isotopes Kinetics Knowledge Label Laboratories Lead Learning Methionine Methods Methylation Methyltransferase Mononuclear Nature New Agents Nitrogen Outcomes Research Oxygen Parents Pathway interactions Pharmaceutical Preparations Productivity Property Reaction Recording of previous events Ring Compound Role Skeleton Spectrum Analysis Structure Testing Therapeutic Therapeutic Agents Work X-Ray Crystallography analog antimicrobial drug azicemicin A catalyst clinical application combinatorial cyclopropane design enzyme mechanism enzyme pathway epoxidase feeding innovation insight member novel novel therapeutics phosphonate public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Many natural products contain cyclopropane, oxirane, or aziridine groups as key structural elements. These three-membered ring moieties are generally stable despite their considerable ring strain. However, the inherent reactivities of these small rings can be released by enzymatic activation. Such activation often leads to reactive intermediates that inhibit the corresponding enzyme, making these three-membered ring containing compounds potential drugs. Although these small ring structures have a long history as therapeutic agents and mechanistic probes, little is known about how they are constructed in nature. To explore the biosynthesis of these strained ring compounds and to facilitate drug design efforts, we have chosen to study several intriguing enzymes involved in oxirane and aziridine formation. These include (S)-2- hydroxypropylphosphonate epoxidase (HppE) and 2-hydroxyethylphosphonate methyltransferase (HepM) in the fosfomycin biosynthetic pathway, and the enzymes catalyzing aziridine ring formation in the azicemicin A biosynthetic pathway. These enzymes were selected for their significant biological roles, their novel catalytic mechanisms, and their potential as catalysts for the combinatorial biosynthesis of new therapeutics. The proposed experiments will address the following specific aims: (1) to investigate the catalytic mechanism of HppE, including the oxygen activation mechanism and the chemical nature of the reaction intermediates; (2) to characterize the catalytic properties of HepM, especially the functions of methylcobalamin and radical- SAM in catalysis, and the mechanism of the methylation reaction; (3) to establish the biosynthetic pathway of aziridine ring formation in azicemicin A, and to characterize the key enzymes involved in the transformation. These studies will not only lead to a better understanding of the catalytic mechanism of the targeted enzymes, but will also provide important insight for designing methods to control and mimic the catalytic functions of related enzymes, many of which are medically relevant. Our results are expected to contribute to the broad field of natural product biosynthesis and mechanistic enzymology, and may also assist future clinical applications for the development of new metabolites using pathway engineering and/or combinatorial biosynthetic methods. PUBLIC HEALTH RELEVANCE: The objective of this application focuses on learning how oxygen and nitrogen containing three-membered ring compounds are biosynthesized and the mechanisms of the key enzymes involved. The insight gained from this work will be useful for the development of new small ring agents having therapeutic potential, and thus will have a positive impact on human health.

描述（由申请人提供）：许多天然产物包含环丙烷，阿昔雷烷或方济嘧啶基作为关键结构元素。尽管有相当大的环应变，但这些三元环部分通常是稳定的。但是，这些小环的固有反应性可以通过酶促激活释放。这种激活通常会导致反应性中间体抑制相应的酶，从而使这些三元环含有潜在药物。尽管这些小环结构作为治疗剂和机械探针的历史悠久，但对它们在自然界的构建方式知之甚少。为了探索这些紧张的环化合物的生物合成并促进药物设计工作，我们选择研究了几种参与铁烷和氮杂氨酸形成的有趣酶。其中包括（S）-2-羟丙基膦酸酯酶（HPPE）和2-羟基乙基膦酸膦酸酯甲基转移酶（HEPM）（HEPM）在Fosfymycin Biosynthetic途径中，以及催化偶氮肽环中二氮杂蛋白的酶形成的酶的酶。这些酶的重要生物学作用，新型的催化机制以及作为新疗法组合生物合成的催化剂的潜力。提出的实验将解决以下特定目的：（1）研究HPPE的催化机制，包括氧激活机制和反应中间体的化学性质；（2）表征HEPM的催化特性，尤其是甲基番茄素和自由基在催化中的功能，以及甲基化反应的机制；（3）建立偶氮蛋白A中副岛环形成的生物合成途径，并表征与转化有关的关键酶。这些研究不仅会更好地理解目标酶的催化机制，而且还将为设计和模仿相关酶的催化功能提供重要的见解，其中许多酶在医学上相关。我们的结果有望为天然产物生物合成和机械酶学的广泛领域做出贡献，并且还可以使用途径工程和/或组合生物合成方法来帮助未来的临床应用，以开发新的代谢产物。公共卫生相关性：本应用的目的是学习如何将含三元环化合物的氧和氮的生物合成以及所涉及的关键酶的机制进行生物合成。从这项工作中获得的洞察力将有助于开发具有治疗潜力的新小环剂，因此将对人类健康产生积极影响。