Toggle Main Menu Toggle Search

Open Access padlockePrints

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin

Lookup NU author(s): Professor Paul RaceORCiD

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. Mupirocin is a clinically important antibiotic produced by Pseudomonas fluorescens NCIMB 10586 that is assembled by a complex trans-AT polyketide synthase. The polyketide fragment, monic acid, is esterified by a 9-hydroxynonanoic acid (9HN) side chain which is essential for biological activity. The ester side chain assembly is initialised from a 3-hydroxypropionate (3HP) starter unit attached to the acyl carrier protein (ACP) MacpD, but the fate of this species is unknown. Herein we report the application of NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays to establish the remaining steps of 9HN biosynthesis. These investigations reveal a complex interplay between a novel iterative or “stuttering” KS-AT didomain (MmpF), the multidomain module MmpB and multiple ACPs. This work has important implications for understanding the late-stage biosynthetic steps of mupirocin and will be important for future engineering of related trans-AT biosynthetic pathways (e.g. thiomarinol).


Publication metadata

Author(s): Winter AJ, Rowe MT, Weir ANM, Akter N, Mbatha SZ, Walker PD, Williams C, Song Z, Race PR, Willis CL, Crump MP

Publication type: Article

Publication status: Published

Journal: Angewandte Chemie - International Edition

Year: 2022

Volume: 61

Issue: 50

Print publication date: 12/12/2022

Online publication date: 13/10/2022

Acceptance date: 13/10/2022

Date deposited: 20/12/2023

ISSN (print): 1433-7851

ISSN (electronic): 1521-3773

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/anie.202212393

DOI: 10.1002/anie.202212393

PubMed id: 36227272


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
BBSRC
BB/L01386X/1
BB/M009122/1
BB/R007853/1
BB/W008823/1
BDCS-2017-50
British Commonwealth
EPSRC
EP/L015366/1

Share