Wednesday, May 8, 2024
5/8/2024
Project Summary/Abstract The scalable and sustainable biosynthesis of terpenoid drugs like cyclopamine and diverse libraries of terpenoid drug candidates will transform the treatment of disease. There are >30,000 unique plant terpenoids and a valuable subset of these natural products have been approved by the FDA approved or are currently in clinical trials for cancer treatment, malaria treatment, symptom relief, and immune system activation. Terpenoids can be biosynthesized in plants through expensive cultivation (i.e., time-, labor-, and land-intensive), but these approaches can exhibit low and hypervariable yields. Plant terpenoids can also be produced by chemical total synthesis and semi-synthesis. However, terpenoids can contain many chiral centers (e.g., 10 in cyclopamine), resulting in complex syntheses with low overall yields. In contrast, the production of terpenoids in engineered microorganisms is scalable, renewable, and inexpensive, often producing complex terpenoids from simple sugars and salts. For example, an artemisinic acid-producing yeast has resulted in 51 million treatments of artemisinin, contributing to the low current cost of artemisinin anti-malarial combination therapies. This proposal aims to establish methods to accelerate the future microbial biosynthesis of medicinal terpenoids. The full 30-step biosynthetic pathway for cyclopamine will be constructed step-by-step in the brewer’s yeast (Saccharomyces cerevisiae) to produce cyclopamine from simple sugars and salts and solve the challenge of sourcing this drug for the treatment of cancer. In addition, S. cerevisiae will be engineered to produce sets of new-to-nature triterpenoids through the combinatorial screening of enzymes with well-characterized activity. The studies will accelerate the microbial biosynthesis of medicinal terpenoids and diverse libraries of terpenoid drug candidates.
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