Xavier Tao Rose Hills
Expanding a Computational Platform for the Engineering of Chimeric Polyketide Synthases
Polyketide synthases (PKSs) are a family of enzyme complexes that synthesize a diverse class of secondary metabolites including clinically important antibiotic, antifungal, and anticancer compounds. In order to accomplish this, PKSs utilize a modular assembly with a wide variety of catalytic building blocks, passing molecular intermediates between modules until a product is finished. Due to their unique modular nature and deterministic mechanisms, PKSs have inspired engineering efforts to biosynthesize various useful new molecules. However, designing active variants still face difficulties due to a lack of understanding for the reasons behind successful or inactive enzymes, frequently resulting in nonfunctional systems. For this reason, my project will expand ClusterCAD, a computational platform that provides sequence and structure search tools useful for identifying parts necessary to build new chimeric PKSs. Specifically, I will annotate new database entries and implement support for irregular catalytic modules. The addition of novel mechanism elucidations and support for new and unusual catalytic domains will ultimately enhance the platform’s ability to guide the engineering of chimeric PKSs.