Tyler McCullough

Ph.D. Student

Areas of Interest

Thesis Mentor:  Janet Smith, Ph.D.

My thesis research will focus on studying the structure and function of the polyketide synthase (PKS) biosynthetic machinery for a variety of natural products using a multidisciplinary approach of cryo-EM, x-ray crystallography, and biochemistry. Type I PKS are organized into modules, with each elongation module containing at the minimum acyl transferase, acyl carrier protein, and ketosynthase domains. Modules may also have a number of additional catalytic domains responsible for the β-keto processing prior to the next extension step. Bioengineers wish to efficiently synthesize novel or modified bioactive compounds via engineered pathways where the substrate specificity is altered or broadened, or where PKS modules can be rearranged or substituted. My work will focus on addressing some of the remaining challenges standing in the way of this goal, including visualizing the overall architecture of the modules, assessing their structural relationship to other type I PKS or fatty acid synthase (FAS), seeing how the module architecture accommodates non-canonical (halogenase, sulfotransferase) domains, and understanding the dynamic intermodule and intramodule interactions at different steps of the biosynthetic pathway.