# Expanding the synthetic utility of natural product biosynthetic enzymes

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $372,693

## Abstract

Project Summary
Oxidative transformations are one of the most utilized classes of reactions, indispensible in the synthesis of
pharmaceutical agents and small molecules used to study biological systems. While significant strides have
been made in developing powerful methods for oxidative reactions, it remains challenging to carry out these
transformations with high levels of chemo-, site- and stereoselectivity on complex molecules. In contrast to
small molecule catalysts and reagents, enzymes from natural product biosynthetic pathways have evolved to
carry out oxidation reactions with high levels of selectivity. The discovery of oxidative enzymatic reactions and
development of the utility of these catalysts has the potential to enable to synthetic strategies and grant us
access to new molecules with potent biological activity. This proposal describes several strategies for
developing robust enzyme-mediated oxidation reactions and leveraging these tools for the streamlined
synthesis of molecules with pharmaceutical potential.
This work takes advantage of the powerful reactivity and selectivity that Nature has evolved within its synthetic
routes to complex secondary metabolites. From this starting point provided by Nature, we (1) characterize the
function of each enzyme and define the substrate flexibility of each enzyme, (2) use structure-guided protein
engineering to alter the innate site- and stereoselectivity of a given catalysts, (3) develop chemomimetic
biocatalytic reactions and (4) utilize strategies to expand the substrate scope of a given enzyme. Together,
these approaches provide a suite of versatile catalysts that will be applied to the synthesis of biologically active
target molecules. The biological properties of these molecules will be evaluated through direct collaborations
with investigators at the University of Michigan Medical School as well as the Center for Chemical Genomics
High Throughput Screening facility at the University of Michigan Life Sciences Institute.
In summary, this proposal describes the development of chemo-, site- and stereoselective oxidative
transformations mediated by biosynthetic enzymes. These methods will directly enable the synthesis of
complex biologically active molecules relevant to human health.

## Key facts

- **NIH application ID:** 9989618
- **Project number:** 5R35GM124880-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alison Narayan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,693
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989618

## Citation

> US National Institutes of Health, RePORTER application 9989618, Expanding the synthetic utility of natural product biosynthetic enzymes (5R35GM124880-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9989618. Licensed CC0.

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