# Structural Studies of Nonribosomal Peptide Synthesis

> **NIH NIH R35** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $395,613

## Abstract

Microbes produce natural products to thrive in unique environments where they face a wide
range of conditions and competing organisms. These diverse molecules are often unique to
individual species and play roles in cellular communication and signaling, interspecies
competition, nutrient acquisition, and virulence. The ability of natural products to function in
the biological setting make them attractive candidates for the discovery of new pharmaceuticals.
Indeed, roughly two-thirds of small molecule drugs are derived from natural products.
Understanding the biosynthesis of unusual natural products will facilitate the analysis of the
thousands of biosynthetic gene clusters with no known product and may lead to the discovery of
new pharmaceutically active molecules. One family of peptide-based natural products is
produced by the multidomain nonribosomal peptide synthetases (NRPSs). Among the hundreds
of NRPS products are the important peptide antibiotics vancomycin and teixobactin, β-lactam
antibiotics like some penicillins and cephalosporins, the genotoxin colibactin, the
immunosuppressant cyclosporin, as well as bacterial siderophores like enterobactin, pyoverdine,
and mycobactin. NRPSs use a remarkable assembly line architecture; multiple protein domains
are joined in a single protein that can be thousands or tens of thousands of residues in length.
During biosynthesis, amino acid building blocks are covalently loaded onto a carrier domain and
delivered to neighboring catalytic domains for peptide extension and modification. The use of
nonproteinogenic amino acids in a ribosome- and mRNA-independent synthesis, as well as
subsequent chemical modification by auxiliary domains, enables the striking diversity of NRPS
products. We propose to continue our biochemical and structural studies to understand the
molecular basis of NRPS function. We will identify the features that govern the efficient
progression through the NRPS structural cycle to allow the delivery of bound substrates in a
coordinated, efficient process. These studies will determine structures of large, multidomain
enzymes in catalytically relevant conformations to understand features that enable this
structural cycle. We will also examine unusual NRPSs to identify the features that endow NRPS
domains with the ability to perform unexpected chemical reactions. We will examine NRPSs
with undetermined biosynthetic mechanism with a particular focus on unusual catalytic
properties of condensation and thioester domains, and will determine the products of
uncharacterized NRPSs from human pathogens.

## Key facts

- **NIH application ID:** 10129975
- **Project number:** 5R35GM136235-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** ANDREW M GULICK
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,613
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129975

## Citation

> US National Institutes of Health, RePORTER application 10129975, Structural Studies of Nonribosomal Peptide Synthesis (5R35GM136235-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129975. Licensed CC0.

---

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