Mupirocin is a clinically important antibiotic produced by NCIMB 10586 that is assembled by a complex -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 -AT biosynthetic pathways (e.g. thiomarinol).
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10947060 | PMC |
| http://dx.doi.org/10.1002/ange.202212393 | DOI Listing |
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