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Alkaloid Biosynthetic Studies

生物碱生物合成研究

基本信息

批准号：
10454892
负责人：
Pinghua Liu
金额：
$ 31.35万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454892
关键词：
Acids Active Sites Aerobic Affect Aging Alkaloids Anabolism Anti-Infective Agents Binding Binding Sites Biochemical Biological Catalysis Chemistry Comparative Study Complex Crystallization Cysteine Data Development Disease Distal Enzymatic Biochemistry Enzyme Activation Enzymes Epoxy Compounds Family Genome Goals Gold Growth Histidine Human Hydrogen Bonding Hydroxylation Iron Kinetics Literature Longevity Mass Spectrum Analysis Methods Mining Modeling Mononuclear Mutation Natural Products Nature Oxidants Oxidation-Reduction Oxides Oxygen Pathway interactions Play Reaction Refsum Disease Reporting Role Site Structure Sulfhydryl Compounds System Tyrosine Work alpha ketoglutarate analytical method anti-cancer base chemical synthesis chlorination computer studies computerized tools cysteine sulfinic acid dehydrogenation enzyme activity epimerization frontier functional group mouse model mutant novel oxidation people of color programs unnatural amino acids

项目摘要

Project Summary / Abstract Alkaloid biosynthetic studies C-H activation is one of the key strategies to introduce structural and functional diversities into natural products in both chemical synthesis and biosynthesis. Non-heme iron enzymes are one of the key classes of C-H activating enzymes. In this work, we will conduct mechanistic studies of several non-hydroxylation reactions catalyzed by non-heme iron enzymes, including endoperoxidation, epoxidation, dehydrogenation, and oxidative C-S bond formation. These functional groups are key to the biological activities of many natural products. In Aim 1, we focus on the distal type of -ketoglutarate dependent non-heme iron enzymes because this is a relatively unexplored class of enzymes. There are two mechanistic models in explaining the activities of these enzymes and we will examine them using carefully selected enzymes (FtmOx1, CnsJ, and PhyH) because these enzymes all have two completely different activities. In Aim 2, we will conduct mechanistic studies on non-heme iron enzymes in ergothioneine and ovothiol biosynthesis. There are two mechanistic models proposed based on theoretical calculations. In this aim, using unnatural amino acid containing enzymes, we will differentiate between the two models.

项目摘要/摘要生物碱生物合成研究 C-H激活是将结构和功能多样性引入自然界的关键策略之一化学合成和生物合成的产品。非血红素型铁酶是一类重要的 C-H激活酶。在这项工作中，我们将对几种非羟化反应进行机理研究由非血红素铁酶催化的反应，包括内过氧化、环氧化、脱氢、氧化C-S键的形成。这些官能团是许多天然化合物生物活性的关键产品。在目标1中，我们专注于依赖于-酮戊二酸的远端类型的非血红素铁酶，因为这是一类相对未被开发的酶。有两种机制模型来解释人的活动这些酶，我们将使用精心挑选的酶(FtmOx1、CnsJ和PhyH)来检测它们因为这些酶都有两种完全不同的活性。在目标2中，我们将进行机械化麦角硫蛋白和卵硫醇生物合成中非血红素铁酶的研究。有两种机械论在理论计算的基础上提出了模型。为了达到这个目的，使用了含有非天然氨基酸的酶，我们将区分这两种模型。