(5dl) Engineered Biosynthesis of Natural Products

Natural products are a large group of complex and structurally diverse compounds with important pharmaceutical applications, such as treating cancer, infectious disease, cardiovascular disease etc. Tetracyclines are a family of natural products with broad-spectrum antibiotic activities. Engineered biosynthesis of tetracycline analogs is an attractive option to accelerate the development of the next generation of tetracycline compounds exhibiting novel antibiotic and anticancer properties, as well as to overcome the current modes of antibiotic resistance. Tetracyclines are aromatic polyketides that are biosynthesized by bacterial type II polyketide synthases (PKS). We sequenced the entire gene cluster of oxytetracycline (oxy) 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 a heterologous host. Many interesting biochemical features in tetracycline biosynthesis, including tetracyclic ring formation, amination, oxygenation and methylation, have been studied extensively by combining in vivo and in vitro analyses. In addition, tetracycline intermediates, shunt products and analogs have been generated and characterized, demonstrating our heterologous host/vector pair can be a useful platform towards the engineered biosynthesis of new tetracycline analogs. Besides tetracycline family, I have also worked on the engineered biosynthesis of various complex natural products of fungal origin.

One of the most fascinating aspects about natural product biosynthesis is the biosynthesis 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 structural diversification and analoging. One of my research interests is to understand and engineer the molecular machinery nature employs during natural products synthesis. The recent sequencing of bacterial and fungal genome provides an unprecedented opportunity for a biosynthetic engineer like me to pursue engineered biosynthesis of natural products. In addition, I am also interested in pathway engineering of other bioactive molecules, and turning a microbe into a dedicated biosynthetic machinery of bioactive molecules or even biofuels will be one of my ultimate research goals.

To train myself in the arena of enzymatic catalysis and biochemistry, I will spend the next two years at Professor Christopher T. Walsh's lab (Harvard Medical School) as a postdoctoral scholar. Combined with my doctoral training in bacterial genetics and metabolic engineering, I will position myself to address some of the most interesting scientific and engineering challenges in biomolecule biosynthesis.