# Designing chemoenzymatic approaches to biologically active molecules enabled by enzyme library screening

> **NIH NIH K99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $125,000

## Abstract

PROJECT SUMMARY
Biocatalysis is quickly emerging a set of synthetic power tools for the direct synthesis of chemical matter. By
leveraging enzymes, Nature’s chemical palette for molecular editing, chemists have been able to readily
decorate molecules with high complexity, in a highly selective fashion. The potential of biocatalysis has been
illustrated in its growing use in the pilot scale preparation of therapeutics to treat serious human illness.
This proposal approaches chemoenzymatic synthesis using biocatalysts from two vantage points. In the first
case, the focus is on retrosynthesis guided enzyme discovery by comparison to known biosynthetic pathways.
This will be used to enable the preparation of polyhydroxylated tropolones, highly oxygenated aromatic small
molecules that have broad bioactivities that span from antimicrobial to antiviral and antineoplastic applications.
In a different vein, biocatalysts will be used to expedite the synthesis of spirocyclic tropolone natural products,
malettinins B, C and E. In both cases, enzymes are borrowed from bacterial and fungal tropolone biosynthesis.
This approach will extend into independent research into the synthesis of spiroisoxazoline small molecules,
compounds with equally potent bioactivities isolated from marine sponges, via library screening of cytochrome
P450 enzymes.
In a different lens, the proposal will also delve into investigative reaction design by searching for hidden reaction
pathways across enzyme families. This approach will first be investigated in the context of amino acid
functionalization by using a library of native pyridoxal phosphate (PLP)-dependent enzymes that perform a wide
range of reactions in Nature. Although the enzymes perform differing reactions, the presence of the PLP cofactor
drives the reactivity. This mentored research approach will be translated into independent research on terpene
cyclase enzyme libraries for the enzymatic synthesis of carbocycles via cationic rearrangement and cyclization
reaction development.

## Key facts

- **NIH application ID:** 10876426
- **Project number:** 5K99GM151479-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kendrick Linwood Smith
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,000
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876426

## Citation

> US National Institutes of Health, RePORTER application 10876426, Designing chemoenzymatic approaches to biologically active molecules enabled by enzyme library screening (5K99GM151479-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876426. Licensed CC0.

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