# Posttranslational Modifications during Natural Product Biosynthesis

> **NIH NIH R37** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $300,120

## Abstract

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a major group of natural
products (NPs) produced in all domains of life. The number of RiPP families continues to expand rapidly
based on genome sequencing. RiPPs a·re well suited for genome mining for new natural products by
heterologous expression of biosynthetic gene clusters (BGCs) and for library generation of cyclic peptides
to recognize diverse targets. Furthermore, RiPPs appear to be widely encoded in the human microbiome
and have recently been implicated in causation and prevention of human disease. For the RiPP field to
advance, a better understanding of the post-translational modification processes is important. Similarly,
tools need to be developed to take advantage of the substrate tolerance of the biosynthetic enzymes. In the
current application we describe our progress towards these goals and our proposed studies for continued
advances. This application focuses mostly on the lanthipeptides, a group of polycyclic peptides with
macrocyclic thioether crosslinks. Individual lanthipeptides have a variety of biological activities including
antimicrobial, antiviral, antifungal and anti-allodynic. At least four different routes to lanthipeptides have
evolved and lanthipeptide BGCs are ubiquitous amongst the RiPP family in sequenced genomes. For one
of these four pathways, substrate recognition is reasonably understood but for the other three this
information is lacking and will be a focus of continued research . Another poorly understood aspect is the
factors that control the ring topology of the multiple thioether rings that are formed and this question will be
a focus of investigation. Furthermore, previous work suggests that lanthipeptide biosynthesis takes place in
enzyme complexes that may require its substrate. A method for catalytically competent covalent
attachment of the substrate to the key enzyme will be used to try and structurally characterize such enzyme
complexes. In addition, the mechanisms of a family of enzymes that make amino acid-derived NPs in a
novel pathway will be investigated and the pathways in which they operate will be determined. Improved
engineering technology to disrupt protein-protein interactions with cyclic peptides will be developed.
RELEVANCE (See instructions):
Based on historical precedent, the most likely group of compounds to deliver new antibiotics to fight
antibiotic resistance are natural products. Genome sequences offer unprecedented access to new natural
products that could be future antibiotics but for this information to be used, biosynthetic enzymes that make
the natural products need to be better understood. This application aims to obtain this information.

## Key facts

- **NIH application ID:** 10397980
- **Project number:** 5R37GM058822-23
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** WILFRED A. VAN DER DONK
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,120
- **Award type:** 5
- **Project period:** 1999-02-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397980

## Citation

> US National Institutes of Health, RePORTER application 10397980, Posttranslational Modifications during Natural Product Biosynthesis (5R37GM058822-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10397980. Licensed CC0.

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