# Accessing the hidden biosynthetic capabilities of fungi

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $351,523

## Abstract

ABSTRACT
Filamentous fungi produce a vast universe of secondary metabolites (SM) with biological activities
that are of central importance for progress in medicine and agriculture. For example, fungal SMs
exhibit cytostatic, immunosuppressant, lipid lowering, or antimicrobial properties. Rapid progress
in sequencing the genomes of filamentous fungi has revealed a very large number of putative
biosynthetic pathways with no known metabolites, suggesting a vast potential for the discovery of
new compounds and activities. However, significant impediments to full characterization of fungal
BGC diversity exist: (a) many SMs are synthesized by ‘non-canonical’ biosynthetic gene clusters
(BGCs) not recognized by bioinformatic algorithms, (b) many BGCs are not expressed in standard
laboratory conditions (e.g. ‘cryptic’ BGCs), and (c) genes for some biosynthetic pathways are not
all clustered and involve more than one locus. Further, there is (d) little understanding of the
genesis of functional BGCs. Our recent results clearly indicate that non-canonical BGCs reveal
genuinely novel structures or unusual biochemistry, that specific fungal differentiation signals
induce global BGC expression and that “hot spots” of recombination generate BGC diversity. In
this grant, we will (i) characterize isocyanide synthase (ICS) BGCs, a recently discovered
family of noncanonical fungal BGCs not recognized by current software algorithms for which we
have preliminary results demonstrating new and exciting biochemistry, (ii) use a fungal
differentiation signal for transcriptomic identification of ‘invisible' BGCs across diverse
fungal taxa and (iii) address the hypothesis that genomic “hot spots” of recombination and
horizontal transfer give birth to new BGCs. Based on the premise that non-canonical gene
clusters are particularly likely to produce chemical entities with a high degree of structural and
functional novelty coupled with two advances able to identify active BGCs and how BGC are
formed, our tool set of comparative transcriptomics, advanced endogenous and heterologous
expression platforms and a recently developed platform for comparative metabolomics will
provide a wealth of new structures, biosynthetic pathways, and biological activities through
expansion of the biology, genetics and chemistry of fungal BGCs. Moreover, insight into BGC
genesis and identification of global BGC induction signals present genuinely new processes to
further the scope of fungal BGC discovery and functional annotation.

## Key facts

- **NIH application ID:** 10379404
- **Project number:** 5R01GM112739-07
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** NANCY P KELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,523
- **Award type:** 5
- **Project period:** 2014-12-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379404

## Citation

> US National Institutes of Health, RePORTER application 10379404, Accessing the hidden biosynthetic capabilities of fungi (5R01GM112739-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10379404. Licensed CC0.

---

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