{Reference Type}: Journal Article
{Title}: Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin.
{Author}: Winter AJ;Rowe MT;Weir ANM;Akter N;Mbatha SZ;Walker PD;Williams C;Song Z;Race PR;Willis CL;Crump MP;
{Journal}: Angew Chem Weinheim Bergstr Ger
{Volume}: 134
{Issue}: 50
{Year}: 2022 Dec 12
暂无{DOI}: 10.1002/ange.202212393
{Abstract}: 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).<BR>Mupirocin is a clinically important antibiotic in which the polyketide fragment, monic acid, is esterified to a 9‐hydroxynonanoic acid (9HN) side chain, which is essential for biological activity. NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays were used to establish how 9HN is assembled through the action of multiple acyl carrier proteins, two ketosynthases and fatty acid β‐keto processing enzymes.