DOW Graduate Seminars: Exploring Natural Product Biosynthetic Pathways for Novel Enzymes and Useful Biocatalysts
|Event Date:||March 4, 2008|
|Speaker:||Dr. Yi Tang|
|Speaker Affiliation:||Department of Chemical & Biomedical Engineering, University of California, Los Angeles|
|Time:||3:30 - 4:30 pm
Microbial and plant natural products are among the most important pharmaceutical compounds known to mankind. These compounds are produced by dedicated metabolic pathways using enzymes that possess exquisite catalytic power. Genome sequencing of many microbial species has revealed tremendous diversity among natural product biosynthetic pathways. Enzymes discovered from these pathways collectively constitute a versatile molecular toolbox that can be utilized towards the synthesis of unnatural variants of natural products. In this talk, I will present our recent progress in exploring the biochemistry of three polyketide biosynthetic pathways. First, we have fully sequenced and characterized the biosynthetic gene cluster of oxytetracycline, a broad spectrum antibiotic. The oxy gene cluster contains several novel enzymes not found in other polyketide biosynthetic pathways, including a nitrogen-inserting enzyme that synthesizes an amidated polyketide backbone. The rare, polar amide starter unit introduces new cyclization chemistry for aromatic polyketides, in which the amide functionality can serve either as a nucleophile in the formation of isoquinolones, or as an electrophilic leaving group facilitating the biosynthesis of benzopyrones. Second, I will discuss the enzymology of fungal polyketide synthases. This class of iterative, multidomain megasynthases is mechanistically distinct from the well-characterized bacterial modular synthases. Using an E. coli expression platform, we have elucidated some of the novel programming rules associated with this large family of enzymes. Lastly, I will discuss the discovery, characterization, and engineering of LovD, an acyltransferase from the lovastatin biosynthetic pathway. We have used this enzyme as a powerful biocatalyst for the synthesis of the blockbuster drug simvastatin. The biocatalytic approach is economically competitive with the currently optimized chemical processes, and is being pursued as an alternative, environmentally friendly method of producing the cholesterol-lowering drug.