# An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2022 · $367,135

## Abstract

Project Summary
Despite substantial advancements in small-molecule catalysis, general methods to control the stereoselectivity
in radical-mediated transformations remain a formidable challenge facing synthetic chemists. On the other hand,
enzymes are known for their ability to exert exquisite control over the stereochemical outcome of the reactions
they catalyze. However, the catalytic repertoire of enzymes has been largely limited to their native biochemistry.
Using an interdisciplinary approach combining ideas and technologies from organic chemistry, organometallic
chemistry, biocatalysis, enzyme engineering and computational modeling, we will reprogram naturally occurring
metalloenzymes to catalyze unnatural radical reactions with excellent stereoselectivity. Capitalizing on the innate
redox property of metallocofactor present in a plethora of natural metalloproteins, we will develop metalloredox
radical biocatalytic reactions with significant synthetic utility. First, we will develop new-to-nature metalloredox
atom transfer radical addition reactions that proceed with excellent diastereo- and enantiocontrol. Second, we
will advance stereoselective radical additions to aromatic compounds in a metalloenzyme-controlled fashion.
Furthermore, enantioselective C-H functionalization reactions involving metalloenzymatically formed nitrogen-
centered radicals will be developed. All the three aims are supported by strong preliminary data gathered in our
laboratory. Together, these novel metalloredox biocatalytic processes constitute a powerful toolbox for the rapid
assembly of diverse bioactive small molecules that are highly valuable in biomedical sciences. Furthermore, the
development of new-to-nature catalytic functions will dramatically broaden the biochemical landscape of
metalloenzymes.

## Key facts

- **NIH application ID:** 10502191
- **Project number:** 1R35GM147387-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Yang Yang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,135
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10502191

## Citation

> US National Institutes of Health, RePORTER application 10502191, An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis (1R35GM147387-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10502191. Licensed CC0.

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