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Updated: Jul 3, 2026
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A Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) Platform for Investigating Peptide Biosynthetic Enzymes
Published on: May 4, 2020
Molecular basis for depsipeptide HDAC inhibitor combinatorial biosynthesis.
Munro Passmore1, Xinyun Jian1,2,3,4, Xinyi Zhao3,4
1Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
Nature Communications
|July 1, 2026
Summary
Researchers identified a new gene cluster for producing hybrid natural products like romidepsin. They discovered an unusual mechanism for combining molecular components, offering insights into combinatorial biosynthesis.
Area of Science:
- Natural Product Biosynthesis
- Enzymology
- Molecular Evolution
Background:
- Polyketides and nonribosomal peptides are crucial natural products with significant medical and agricultural uses.
- Bacterial modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) share enzymatic logic, enabling the creation of hybrid molecules.
- Hybrid molecules, such as the HDAC-targeting drug romidepsin, combine a conserved Zn2+-binding pharmacophore with a variable peptide cap.
Purpose of the Study:
- To identify the biosynthetic gene cluster responsible for FR-901375 production in *Pseudomonas chlororaphis subsp. piscium* DSM 21509.
- To elucidate the subunit docking mechanism enabling the interaction between conserved pharmacophore and variable cap biosynthetic machineries in hybrid PKS-NRPS systems.
- To gain insights into the evolutionary mechanisms driving hybrid polyketide-nonribosomal peptide combinatorial biosynthesis.
Main Methods:
- Gene proximity searching to identify the FR-901375 biosynthetic gene cluster.
- Comparative analysis of PKS-NRPS systems involved in related depsipeptide HDAC inhibitors.
- Experimental validation including crosstalk assays, mutagenesis, AlphaFold predictions, and carbene footprinting.
Main Results:
- Identification of the FR-901375 biosynthetic gene cluster in *P. chlororaphis subsp. piscium*.
- Evidence suggesting an unusual subunit docking modality for hybrid PKS-NRPS assembly.
- Experimental data supporting the proposed interaction mechanism between different biosynthetic modules.
Conclusions:
- The study reveals a novel biosynthetic pathway for hybrid natural products.
- An unusual docking mechanism facilitates the assembly of complex hybrid molecules.
- Findings contribute to understanding the evolution of combinatorial biosynthesis in bacteria.
