CBE colloquia - Molecular Mechanism of Enzyme-Catalyzed Pericyclic Reactions

Pericyclic reactions refer to synergistic reactions with cyclic transition states, which are often used in the synthesis of natural products to efficiently construct multiple carbon-carbon bonds with good stereoselectivity and regioselectivity. In collaboration with Yi Tang's research group and Ken N. Houk's research group at UCLA, we identified a family of pericyclases, including the multifuncational pericyclase LepI, the first characterized of Alder-ene reaction enzyme PdxI, and its homologous protein EpiI which catalyzes the hetero-Diels-Alder reaction. We solved the x-ray crystal structures of SAM-bound LepI and in complex with a substrate analogue, the product leporin C, and a retro-Claisen reaction transition-state analogue to understand the structural basis for the multitude of reactions. Structural and mutational analysis reveals how nature evolves a classic methyltransferase active site into one that can serve as a dehydratase and a multifunctional pericyclase. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels–Alder and vice versa. More recent progress on glycosylated and iminium-based pericyclases will also be reported.