This action funds an NSF Minority Postdoctoral Research Fellowship for FY 2008. The fellowship supports a research and training plan in a host laboratory for the Fellow who also presents a plan to broaden participation in biology. The title of the research and training plan for this fellowship to Charles E. Stewart is "Structural basis for the evolution of novel functions in type III polyketide synthases" The host institution for this research is the Salk Institute and the sponsoring scientist is Dr. Joseph Noel.
Polyketide synthases are enzymes that produce an amazing array of natural products in plants and bacteria that find important uses in medicine and agriculture. The diversity of these compounds is related to the variety of cyclization mechanisms used by the enzymes during biosynthesis. This research investigates the structural changes in polyketide synthases that show different functions and result in different products. The 3-dimensional structure of two closely related polyketide synthases with different cyclization patterns are being studied using x-ray crystallography. Comparison of these structures will help identify the specific amino acids responsible for the different cyclization patterns.
The training objectives are to gain skills in enzymology and structural biology, especially as they relate to natural products, scientific ethics and science communication. The broader impacts include increasing the number of minorities through innovative outreach programs targeting students of various ages and education from the junior high to the post-doctoral level. This research will have broad impacts across academic disciplines, in particular the fields of biology, chemical biology, and natural product chemistry.
Type III polyketide synthases are enzymes found primarily in plants that make a diverse array of chemical compounds that are important to both agriculture and the environment. The goals of this project where to discover and study the relationship between structure and function in biphenyl synthases, an evolutionary distinct group of type III polyketide synthases. X-ray crystallography was used to solve the 3D protein structure of biphenyl synthase. Additionally, structures of the protein binding to its substrate and product were also solved. These structures revealed that the active site in biphenyl synthase is considerably smaller than similar enzymes. To gain insight into the intermediate stages of the enzyme reaction (the stages between starter substrate binding and final product releasing), structures of the protein bound with chemical analogs of hypothetical intermediates were obtained via x-ray crystallography. These chemical insight provided insight into how the protein control the unstable chemical intermediate during its reaction. Lastly, structures of several related enzymes, namely stilbene synthases and chalcone synthases, were solved and used for a comparative structural analysis of this enzyme family. One of the key broader impacts of this project was the participation of underrepresented groups. The PI mentored two minority high school students as part of a summer research internship program organized by the host institution. Additionally, the PI served as a judge for an undergraduate research competition organized by the National Society for Minorities in Agriculture and Natural Resources (MANRRS). Lastly, the PI served as a post doc-liaison on the Student Leadership Council within the NSF Engineering Research Center for Biorenewable Chemicals administered by Iowa State University.
