Structural and Functional Analysis of the Plant Phenylpropanoid Biosynthetic Pathway

植物苯丙素生物合成途径的结构和功能分析

• 批准号: 0236027
• 负责人: Joseph Noel
• 金额: $ 69万
• 依托单位: The Salk Institute for Biological Studies
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0236027&HistoricalAwards=false
• 关键词: Structural; Functional; Analysis; Plant; Phenylpropanoid

Plant phenylpropanoids including flavonoids and stilbenes comprise a structurally diverse group of secondary metabolites that play vital roles in the interaction of plants with their surrounding environment. The utility of these compounds in plants varies widely and includes roles as structural polymers, defense barriers, defense chemicals synthesized in response to microbial, insect, and herbivore predation, signaling molecules for nitrogen-fixing rhizobia bacteria, UV-protective agents, and pigments. In addition to their role in plant physiology, phenylpropanoids possess a number of properties that have proven useful to the pharmaceutical, food, agricultural, and nutritional industries. A major goal of this project is to understand the molecular mechanisms underlying the biosynthesis of plant phenylpropanoids. The current objectives of this research are to examine the functional diversity of the chalcone synthase (CHS) / stilbene synthase (STS) superfamily of plant polyketide synthases involved in the initial stages of flavonoid biosynthesis using both x-ray crystallography and enzymological studies, the mechanism, stereochemistry, and selectivity of chalcone isomerase (CHI)-mediated flavanone formation in both chalcone and deoxychalcone biosynthetic pathways, the structure and mechanism of chalcone reductase (CHR), and the energetic and architectural features of multienzyme complex formation involving CHS, CHI, and/or CHR during flavonoid and isoflavonoid biosynthesis using surface plasmon resonance and TROSY-NMR. These studies will elucidate the mechanisms governing phenylpropanoid production in plants and in particularly will relate the biosynthetic diversity of these pathways to on-going evolutionary change that leads to this biologically important form of chemical diversity. Significantly, the broader impacts resulting from the proposed research activities include a significant training component that involves the exclusive participation of both graduate (PhD) and undergraduate (BS) students in groups under represented in scientific research. In addition, key scientific findings generated by this research will be disseminated to the public principally through annual lectures organized through an evening seminar series for the general public that discusses in lay terms the science and significance of the on-going publicly supported work at the Salk Institute. Recently, key findings obtained during the initial stages of this project described the benefits of understanding plant secondary metabolism for mankind with regard to agriculture, disease prevention, and drug discovery. A number of plant-derived phenylpropanoids are valuable medicinal agents. Moreover, the regular dietary consumption of phenylpropanoid-derived compounds including lignans, stilbenes, and (iso)flavonoids has considerable health benefits including lowered risk factors for both cancer and coronary artery disease. The enzyme scaffolds that are used by plants to create these small molecules serve as novel and useful starting points to create new molecular entities for drug discovery using a novel approach that includes structural biology and genomics. Most importantly, all organisms utilize chemical diversity to live and prosper in harsh and challenging environments. While an organism's protein and gene diversity have captured the public's attention over the last several years, ultimately, chemical diversity and an organism's adapting metabolism create "endogenous drugs" that all species exploit for survival. This project will generate information with which to better understand the molecular basis for this on-going process of evolutionary change at the chemical level. In turn, such information not only provides mankind with an understanding of organismal evolution at the molecular and metabolic level, but also provides a framework for manipulating this framework for the creation of new chemicals for drug discovery, improvements in nutrition, and ultimately, a healthier life.

植物苯丙素（包括类黄酮和芪）由一组结构多样的次生代谢物组成，在植物与其周围环境的相互作用中发挥着至关重要的作用。这些化合物在植物中的用途差异很大，包括作为结构聚合物、防御屏障、响应微生物、昆虫和草食动物捕食而合成的防御化学物质、固氮根瘤菌的信号分子、紫外线防护剂和色素。除了在植物生理学中的作用外，苯丙素还具有许多已被证明对制药、食品、农业和营养行业有用的特性。该项目的一个主要目标是了解植物苯丙素生物合成的分子机制。本研究当前的目标是利用 X 射线晶体学和酶学研究，检查参与类黄酮生物合成初始阶段的植物聚酮合酶 (CHS)/二苯乙烯合酶 (STS) 超家族的功能多样性，以及查尔酮异构酶 (CHI) 介导的黄烷酮的机制、立体化学和选择性。 使用表面等离子体共振和 TROSY-NMR 来了解查耳酮和脱氧查耳酮生物合成途径中的形成、查耳酮还原酶 (CHR) 的结构和机制，以及黄酮类和异黄酮类生物合成过程中涉及 CHS、CHI 和/或 CHR 的多酶复合物形成的能量和结构特征。这些研究将阐明植物中苯丙素生产的控制机制，特别是将这些途径的生物合成多样性与持续的进化变化联系起来，从而导致这种生物学上重要的化学多样性形式。值得注意的是，拟议的研究活动产生的更广泛影响包括重要的培训部分，其中涉及研究生（博士）和本科生（BS）学生在科学研究中的代表性群体的独家参与。此外，这项研究产生的关键科学发现将主要通过年度讲座向公众传播，这些讲座是通过为公众举办的晚间研讨会系列举办的，以通俗的方式讨论索尔克研究所正在进行的公众支持的工作的科学性和意义。最近，该项目初始阶段获得的重要发现描述了了解植物次生代谢对人类在农业、疾病预防和药物发现方面的好处。许多植物来源的苯丙素是有价值的药物。此外，定期饮食摄入苯丙素衍生化合物（包括木酚素、芪和（异）黄酮类化合物）具有相当大的健康益处，包括降低癌症和冠状动脉疾病的危险因素。植物用来产生这些小分子的酶支架可以作为新颖且有用的起点，使用包括结构生物学和基因组学在内的新颖方法来创建用于药物发现的新分子实体。最重要的是，所有生物体都利用化学多样性在恶劣和充满挑战的环境中生存和繁荣。虽然生物体的蛋白质和基因多样性在过去几年中引起了公众的关注，但最终，化学多样性和生物体的适应新陈代谢创造了所有物种赖以生存的“内源性药物”。该项目将生成信息，以便更好地了解化学水平上持续进化变化过程的分子基础。反过来，这些信息不仅让人类在分子和代谢水平上了解有机体进化，而且还提供了一个框架来操纵这个框架，以创造新的化学物质，用于药物发现、改善营养，并最终实现更健康的生活。