Louisiana State University Shreveport
Elucidation of Plant-Derived Drug Biosynthetic Pathways and Molecular Mechanisms as Anticancer Agents
Shile Huang, Louisiana State University Health Shreveport
Full Project (May 1, 2021 - April 30, 2024)
Pilot Project (May 1, 2019 - August 18, 2020)
Medicinal plants produce highly diverse metabolites that have been used in cancer treatment. Two important chemotherapeutic agents, vinblastine and camptothecin, classified as monoterpene indole alkaloids (MIAs) are isolated from plant species Catharanthus roseus and Camptotheca acuminata, respectively. Despite their wide applications in the clinic, access to these drugs still relies on the extraction from the plants with low yields. In order to increase accessibility to these pharmaceuticals, the functional characterization of MIA biosynthetic enzymes is required as the prerequisite for metabolic engineering approach. The chemical diversity of MIAs, especially those with important pharmaceutical properties could also be further increased in metabolic engineering efforts using microbial systems. MIA biosynthetic pathways provide an excellent model of how a chemical diversity can be generated from a single central intermediate, known as strictosidine. In this project, we integrate genomic, transcriptomic, and metabolomic approaches to elucidate biosynthetic steps downstream of strictosidine formation that give rise to different MIAs with anticancer activities and other significant pharmacophores. The discovery of genes encoding the MIA biosynthetic pathways will also permit the use of heterologous expression of these compounds and their analogs for novel potential therapeutic implication. Their unique chemical structures and diverse pharmacological activities may further provide new leads for effective anticancer drugs. We aim to develop microbial systems for increased production of MIA camptothecin and its significant analogs that may exhibit anticancer activities as well as to elucidate their mechanism of action.