Engineered Biosynthesis of Bacterial Aromatic Polyketides for Pharmaceutical Applications

Featuring Wenjun Zhang, M.S.
Ph.D. Candidate, Department of Chemical and Biomolecular Engineering Department
UCLA

Location:  McDonnell Douglas Engineering Auditorium
Free and open to the public

Abstract:
Polyketides are a large group of complex and structurally diverse natural products with important pharmaceutical applications, such as treating cancer, infectious disease, cardiovascular disease, etc.  One of the most fascinating aspects about natural product biosynthesis is the generation of the rich and diverse chemical structures, which are difficult to synthesize de novo using synthetic approaches.  Therefore, biosynthetic engineering represents a potent solution towards chemical structural diversification and analog production. 

One of Zhang's research projects is to understand and engineer the molecular machinery nature employs during tetracycline synthesis.  Tetracyclines are a family of bacterial aromatic polyketides with broad-spectrum antibiotic activities, band anticancer properties, as well as to overcome the current modes of antibiotic resistance.  They sequenced the entire gene cluster of the oxytetracycline (oxy) polyketide synthase (PKS) from Streptomyces rimosus, and identified the minimal oxy PKS, the initiation module, the immediate tailoring enzymes, and the further downstream tailoring enzymes responsible for anhydrotetracycline (ATC) biosynthesis in the heterologous host Streptomyces coelicolor.  Many interesting biochemical features in tetracycline biosynthesis, including tetracyclic ring formation, amination, oxygenation and methylation, were studied extensively by combining in vivo and in vitro analyses. In addition, tetracycline intermediates, shunt products and analogs were generated and characterized, demonstrating our heterologous host/vector pair as a useful platform toward the engineered biosynthesis of new tetracycline analogs.

Zhang's second research project is to reconstitute the biosynthesis of bacterial aromatic polyketides in the genetically superior host Escherichia coli.  E. coli has been utilized as a dedicated biosynthetic microbial factory with high degrees of success for nearly all major classes of natural products.  Nonetheless, attempts to synthesize the pharmaceutically important bacterial aromatic polyketides had previously been hindered due to the insolubility of key components of bacterial aromatic PKSs.  By extracting and reassembling the minimal PKS from a non-reducing fungal megasynthase, they promoted the cross-talk between the bacterial and fungal PKSs, and synthesized complex bacterial aromatic polyketides in E. coli for the first time.  This paves the way for engineered biosynthesis of bacterial aromatic polyketides in the workhorse organism E. coli, and also provides immense opportunities toward biochemical understanding and protein engineering of aromatic PKS enzymes.

About the Speaker:
Wenjun Zhang is currently a doctorial candidate in the Department of Chemical and Biomolecular Engineering at the University of California, Los Angeles, under the mentoring of Professor Yi Tang.  She received her B.S. degree in biochemistry from Nanjing University in 2002, and obtained her M.S. in biochemistry and molecular biology from Nanjing University in 2004.  She is currently supported by a UCLA Dissertation Year Fellowship and Nell I. Mondy Fellowship from Sigma Delta Epsilon/Graduate Women in Science.