Engineering Saccharomyces Cerevisiae For The Production Of Plant Derived Pharmaceuticals

Download or read book Engineering Saccharomyces Cerevisiae for the Production of Plant-derived Pharmaceuticals written by Isis Jean Trenchard and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Natural products and their derivatives comprise over 60% of all drugs currently on the market, and natural product pharmaceuticals have been the subject of renewed interest to revitalize drug discovery pipelines. Plant secondary metabolites are a significant source of bioactive compounds. The discovery and screening of new natural products from plants is difficult, however, because many compounds exist only in trace amounts and the methods for isolating and purifying these compounds from the native plant hosts are generally inefficient. Microbial biosynthesis of plant metabolites is an exciting alternative production platform that provides several distinct advantages over the native plant hosts, including well-developed genetic tools for pathway expression and manipulation, fast growth rates, and established large-scale culture methods. Here we describe engineering Saccharomyces cerevisiae as a microbial production platform for the benzylisoquinoline alkaloids (BIAs), a large class of plant secondary metabolites that exhibit a wide range of pharmacological activities, including anti-HIV, anticancer, and antimicrobial activities. We engineered strains capable of producing protoberberine, protopine, benzophenanthridine and bisbenzylisoquinoline alkaloids. The number and types of chemical transformation steps achieved in this work represent one of the most complex examples in the field of metabolic engineering. In addition, we have developed strategies for the microbial expression of plant cytochrome P450s including expression methods and culture condition optimizations. Through engineering BIA biosynthetic pathways in yeast we have sought to create a reliable and scalable source of valuable drugs and drug candidates and develop generalizable optimization strategies that will broadly advance the development of microbial production platforms for plant natural products.