A Systems Approach Toward Elucidating The Molecular Basis Of Tropane Alkaloid Metabolism

Abstract

Tropane and granatane alkaloids are key mediators of interspecies plant communication and valued by society for their pharmacological properties. Beyond their biological significance, the biocatalytic steps needed to generate tropane and granatane chemical scaffolds is not completely understood. This lack of knowledge of biosynthetic steps as well as kinetic and thermodynamic properties diminishes the scientific community's understanding of the chemistry of life. Tropane and granatane alkaloid metabolism consists of three modules: a first ring closure that forms a reactive N‐heterocyclic intermediate, a second ring closure that generates the tropane chemical scaffold and lastly modifications of the core chemical scaffold. The overarching question guiding this research is, how are the critical ring forming enzymes leading to these bicyclic compounds functioning at the molecular level? While tropane alkaloid metabolism has historically been studied in the Solanaceae, recent evidence indicates that non‐solanaceous species have independently evolved tropane metabolism using alternative biosynthetic machinery. Moreover, granatane alkaloids are structurally similar to tropane alkaloids and are hypothesized to use biocatalytic steps similar to those used to produce tropane alkaloids. Collectively, the tropane and granatane alkaloids constitute a comparative system for studying the mechanistic basis for the emergence and diversification of specialized metabolic enzymes. An integrated approach using biochemical, biophysical and molecular genetic currently being used to discover the molecular determinants of the bicyclic ring in tropane and granatane biosynthesis. Results from both the early and the terminal steps in the respective tropane and granatane pathways have begun to fill‐in gaps in our knowledge of their respective biosynthetic pathways as well as discover novel enzymes and divergent evolutionary mechanisms. For example, current data supports the hypothesis that a Type III Polyketide synthase is responsible for the extension off the first ring and ultimate formation of the second ring in the bicyclic tropane or granatane nucleus. We have identified Type III PKS enzymes and the genes encoding them from members of the Erythroxylaceae, Solanaceae, and Lythraceae. These enzymes all produce their respective predicted non‐cylclized polyketide enzyme product while sharing closer identity with PKS enzymes from within their own lineages.Support or Funding InformationThis research is funded via the National Science Foundation of the United States of America award ID. 1714236This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.