# Investigating biosynthetic enzymes to enhance natural product discovery

> **NIH NIH R35** · UNIVERSITY OF ALABAMA IN TUSCALOOSA · 2024 · $360,853

## Abstract

Project Summary
Natural products (NPs) have diverse complex structures and play a vital role in drug discovery and development.
Although the rate of discovery of natural products has increased significantly, traditional bioactivity-guided
discovery methods frequently lead to the re-discovery of known compounds. Therefore, genetic information-
driven isolation is becoming a powerful tool to uncover novel NPs. Genome mining efforts that target genes
responsible for the biosynthesis of core structures of major NP classes, has identified tens of thousands of new
biosynthetic gene cluster (BGC) families predicted to produce novel compounds. While this method has been
very successful in predicting compounds from these major classes, it is limited to those scaffolds and cannot
identify other specific features of NP structures. Furthermore, these methods will overlook “hidden” BGCs that
do not contain traditional core biosynthetic machinery, leaving a major gap in NP discovery. The first direction of
this proposal aims to use specialized genome mining strategies that target NP glycosyltransferases to identify
uncharacterized BGCs that produce bioactive glycosylated NPs with distinct core structures. Consequently,
identified compounds will be directly linked to their BGC and likely have biosynthetic pathways that consist of
unique enzymes and biochemical reactions. The second direction of this proposal is to interrogate the activities
and mechanisms of new biosynthetic enzymes. These will include enzymes discovered in direction one, along
with enzymes responsible for the biosynthesis of the aminocyclitol found in hygromycin A, that contains a rare
modification essential for bioavailability. Subsequent re-integration of newly characterized biosynthetic enzymes
into standard or specialized genome mining methods will assist in annotating and identifying additional BGCs to
improve NP discovery. In addition, these enzymes will add to the growing toolbox of biocatalytic reactions
exploited for unnatural small molecule biosynthesis. Ultimately, this research program will significantly advance
NP and enzymology research to boost drug discovery and development for the benefit of human health.

## Key facts

- **NIH application ID:** 10891624
- **Project number:** 5R35GM151137-02
- **Recipient organization:** UNIVERSITY OF ALABAMA IN TUSCALOOSA
- **Principal Investigator:** Melanie Ann Higgins
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,853
- **Award type:** 5
- **Project period:** 2023-08-05 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891624

## Citation

> US National Institutes of Health, RePORTER application 10891624, Investigating biosynthetic enzymes to enhance natural product discovery (5R35GM151137-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10891624. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*