CAREER: Engineered SAM-Dependent Enzymes for Stereoselective Alkylation Reactions

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This award is funded in whole under the American Rescue Plan Act of 2021 (Public Law 117-2).With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Yang Yang of the University of California-Santa Barbara (UCSB) is working with a team of graduate and undergraduate students to discover and develop biocatalysts for selective C-alkylation reactions. Enzymes are protein biocatalysts that have naturally evolved to catalyze chemical reactions, often with excellent chemo-, regio- and stereoselectivities. These biocatalysts function in water under exceptionally mild conditions, thus allowing chemical synthesis to be carried out in a more sustainable fashion. Furthermore, enzymes are easily produced on a large scale using microbial hosts and have been exploited recently for applications in chemical manufacturing and pharameutical process chemistry. It is desirable to discover and engineer new classes of biocatalysts to catalyze synthetically significant reactions with enhanced efficiency and selectivity. Dr. Yang and his students will exploit their abilities in organic synthesis, physical organic chemistry, enzymology and protein engineering to investigate and discover efficient new biocatalysts for selective C-alkylation reactions, alpha-to a carbonyl group, a process that is widely used in the synthesis of organic compounds. In partnership with ongoing outreach programs at UCSB, Dr. Yang will lead hands-on workshops to introduce local 7-12th grade students to the key concepts and applications of chemical synthesis and biocatalysis.Combining ideas and technologies from organic chemistry, genome mining and protein engineering, Dr. Yang and his students aim to discover and develop new biocatalysts to facilitate selective alkylation reactions. Despite the synthetic utility to these transformation, aside from examples using organocatalysis, there are relatively few general catalytic asymmetric methods for C-alkylation adjacent to a carbonyl group. To address this challenge, Dr. Yang and his group are developing a fully biocatalytic platform consisting of a set of engineered alkyl transfer enzymes to facilitate highly stereoselective alkylation processes using abundant and readily available alkylation reagents. This biocatalytic alkylation platform, once fully developed, is expected to allow for a range of useful chiral building blocks to be synthesized conveniently. Broader impacts of this endeavor include the hands-on exposure of students from underrepresented groups to science, technology, engineering, and mathematics (STEM) careers, as well as planned outreach focused at the local level and on underserved communities.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.