How Nature Repurposes Protein Folds to Catalyze Pericyclic Reactions, and New Computational Methods to Understand Pericyclase Mechanisms

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Houk and Tang of the University of California, Los Angeles are studying the development of a new class of enzymes, proteins that catalyze reactions that occur in a single step and produce complex polycyclic natural substances. These enzymes are called pericyclases. Many of these will be discovered and studied experimentally in the Tang lab and explored with sophisticated computer methods in the Houk lab. The groups will work together to show how these enzymes accelerate these chemical reactions, and control the formation of one of the many possible products that could be produced from a substrate. This information is of value for the future engineering of catalysts for production of useful substances. The young scientists working on these projects in the Houk and Tang labs will develop skills in both experiment and theory, and participate in outreach, such as mentoring high school and undergraduates to begin research, and developing teaching materials to be used to excite grade school and college students to undertake studies to become scientists. Discovering new enzymes and functions are central to understanding chemistry of life processes. This proposal will decipher the underlying mechanisms of an emerging family of enzymes known as pericyclases. The goals of this proposal are to characterize the mechanisms by which natural product biosynthetic reactions are catalyzed by pericyclases, to understand how Nature evolved common protein folds into dedicated pericyclases, and to establish whether electrocyclases exist in Nature. The Houk and Tang groups will expand the fundamental understanding of enzyme catalysis and broaden the scope of catalysis to the pericyclases. Methods will be perfected for the identification of enzyme mechanisms even in the absence of experimental structural information. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.