Areas of Interest
Polyketide natural products constitute a broad range of chemically diverse compounds, many of which display pharmacological properties. Type I polyketide synthases (PKSs) are large enzymatic assembly lines consisting of individual multi-domain PKS modules. Due to the modular nature of type I PKSs, there is significant interest in reengineering these biosynthetic pathways to enzymatically produce novel polyketides for both drug discovery and the production of other high value compounds. Bioengineering efforts have created new molecules, but at quite low efficiencies. One hurdle limiting the success of pathway engineering is the lack of structural information for full PKS modules. Many crystal structures are available for excised PKS domains, but little is known regarding the domain arrangement within a module. Instead, module organization has been inferred from a crystal structure of the homologous mammalian fatty acid synthase (FAS). However, variations between FAS and PKS, such as domain combinations, domain oligomer state, inter-domain linkers, and PKS inter-modular docking domains, hint that their architectures may differ. Recently, the Smith lab in collaboration with the Skiniotis and Sherman labs, has solved the first structure of a PKS module via cryo-electron microscopy (EM). The EM maps revealed a PKS module with a strikingly different architecture than the FAS crystal structure. However, this reconstruction is representative of only one type of PKS module. Therefore, I am studying the structures of PKS modules with a variety of domain combinations using both x-ray crystallography and EM.
Honors & Awards
Cellular Biotechnology Training Program (2014)
Anthony and Lillian Lu Award (2015)