Structural and Functional Analysis of the Plant Phenylpropanoid Biosynthetic Pathway

The Salk Institute For Biological Studies, La Jolla CA

Investigators

Abstract

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.