The specificity of intermodular recognition in a prototypical nonribosomal peptide synthetase depends on an adaptor domain

authored by: Megha N. Karanth, John P. Kirkpatrick, Joern Krausze, Stefan Schmelz, Andrea Scrima, Teresa Carlomagno
Abstract: In the quest for new bioactive substances, nonribosomal peptide synthetases (NRPS) provide biodiversity by synthesizing nonproteinaceous peptides with high cellular activity. NRPS machinery consists of multiple modules, each catalyzing a unique series of chemical reactions. Incomplete understanding of the biophysical principles orchestrating these reaction arrays limits the exploitation of NRPSs in synthetic biology. Here, we use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry to solve the conundrum of how intermodular recognition is coupled with loaded carrier protein specificity in the tomaymycin NRPS. We discover an adaptor domain that directly recruits the loaded carrier protein from the initiation module to the elongation module and reveal its mechanism of action. The adaptor domain of the type found here has specificity rules that could potentially be exploited in the design of engineered NRPS machinery.
Organisation(s): Institute of Organic Chemistry
External Organisation(s): University of Birmingham
Helmholtz Centre for Infection Research (HZI)
Type: Article
Journal: Science advances
Volume: 10
ISSN: 2375-2548
Publication date: 21.06.2024
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: General
Electronic version(s): https://doi.org/10.1126/sciadv.adm9404 (Access: Open)

BibTeX

@article{0a67b047ee7b4d709e72100fce8f18db,
title = "The specificity of intermodular recognition in a prototypical nonribosomal peptide synthetase depends on an adaptor domain",
abstract = "In the quest for new bioactive substances, nonribosomal peptide synthetases (NRPS) provide biodiversity by synthesizing nonproteinaceous peptides with high cellular activity. NRPS machinery consists of multiple modules, each catalyzing a unique series of chemical reactions. Incomplete understanding of the biophysical principles orchestrating these reaction arrays limits the exploitation of NRPSs in synthetic biology. Here, we use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry to solve the conundrum of how intermodular recognition is coupled with loaded carrier protein specificity in the tomaymycin NRPS. We discover an adaptor domain that directly recruits the loaded carrier protein from the initiation module to the elongation module and reveal its mechanism of action. The adaptor domain of the type found here has specificity rules that could potentially be exploited in the design of engineered NRPS machinery.",
author = "Karanth, {Megha N.} and Kirkpatrick, {John P.} and Joern Krausze and Stefan Schmelz and Andrea Scrima and Teresa Carlomagno",
note = "Publisher Copyright: copyright {\textcopyright} 2024 the Authors, some rights reserved; exclusive.",
year = "2024",
month = jun,
day = "21",
doi = "10.1126/sciadv.adm9404",
language = "English",
volume = "10",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "25",
}