# Discovery and Characterization of Natural Product Systems

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $381,095

## Abstract

Project Summary. In this competing renewal of R35 GM118101, we propose to focus on investigating and
developing biocatalytic systems that generate complex natural products with high potential as therapeutic
agents. This program has been highly productive with 34 publications over the past four years. Major progress
continues toward studies on the function and structure of modular polyketide synthases (PKSs) from bacteria. A
second thematic area involves studies on diverse bacterial and fungal indole alkaloid pathways for which we
have reported important achievements on characterizing biosynthetic enzymes that catalyze pericyclic (e. g.
Cope, Diels-Alder) reactions. We plan to build on these studies and also expand work on allied tailoring reactions
for indole alkaloid structural diversification.
 Our work in the type I PKS area will focus on function and structure of key catalytic domains that we have
identified to be gatekeepers in the catalytic cycle. By employing natural and unnatural advanced polyketide chain
elongation intermediates with late stage PKS modules, we plan to develop methods to expand the biocatalytic
potential of these remarkable molecular machines for assembly of macrolactone structures. Further glycosylation
and late-stage hydroxylation/epoxidation methods will be employed to generate next generation macrolides for
testing against a range of antibiotic-resistant human pathogens.
 Our work in the microbial indole alkaloids will focus on natural products whose core ring systems are derived
from biocatalytic pericyclic reactions. Mechanistic understanding of these unusual processes is rapidly emerging,
and their apparent flexibility indicates high potential for metabolite structural diversification. These efforts will be
augmented by exploring late-stage tailoring enzymes capable of further modifying core indole alkaloid structures
to generate a range of biologically active products with significant pharmaceutical potential.

## Key facts

- **NIH application ID:** 10418743
- **Project number:** 5R35GM118101-07
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** DAVID H SHERMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,095
- **Award type:** 5
- **Project period:** 2016-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418743

## Citation

> US National Institutes of Health, RePORTER application 10418743, Discovery and Characterization of Natural Product Systems (5R35GM118101-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418743. Licensed CC0.

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