Manipulation of key enzymes responsible for generating basic skeletons of pharmaceutically important secondary metabolites (e.g. polyketides and isoprenoids) leads to production of biologically active, supra-natural products with remarkable structural diversity. Two specific aims of the proposed research are (1) structure-based rational design of mutant enzymes of plant polyketide synthases and squalene cyclases with altered substrate and product specificities, and (2) exploration of catalytic potential of the enzymes by using synthetic substrate analogs.