New enzyme-catalyzed reactions from catalytically promiscuous ancestral enzymes

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In this award from the Chemistry of Life Processes Program in the Division of Chemistry and the Biotechnology, Biochemical, and Biomass Engineering Program in the Chemical, Bioengineering, Environmental, and Transport Systems Division, Drs. Romas Kazlauskas and Antony Dean, from the University of Minnesota, Twin Cities, will resurrect ancestral generalist enzymes using gene synthesis. The targets are ancestors of hydroxynitrile lyases, which catalyze a carbon-carbon bond formation: addition of cyanide to aldehydes. The research will test the ability of these ancestral enzymes to catalyze other carbon-carbon bond forming reactions and optimize them for different reactions. A current challenge in chemical synthesis is to assemble complex molecules catalytically, and stereoselectively while using environmentally friendly conditions and reagents. Biocatalysis is a potential solution, but the reaction range of current biocatalysts is limited. This work constitutes a new approach to discover biocatalysts that catalyze unnatural reactions, which uses carbon-carbon bond forming reactions as a test case. Studies of resurrected ancestral enzymes seek to answer basic questions of how new enzymes and metabolic pathways evolve. In addition, resurrected ancestral enzymes may be starting points for engineering new enzymes because ancestral enzymes can catalyze additional chemical reactions, including potentially useful unnatural reactions. The proposed work will train under-graduate, graduate and postdoctoral students in a chemical approach to solving interdisciplinary problems, actively recruit and include students from groups underrepresented in chemical sci-ences, and support outreach to elementary school students.