In vivo Mutational Analysis of the Mupirocin Gene Cluster Reveals Labile Points in the Biosynthetic Pathway: the 'Leaky Hosepipe' Mechanism

J Wu, J Hothersall, C Mazzetti, Y O'Connell, J.A Shields, A.S Rahman, R.J Cox, J Crosby, T.J Simpson, C.M Thomas, C.L Willis

Research output: Contribution to journalArticle (Academic Journal)

29 Citations (Scopus)

Abstract

A common feature of the mupirocin and other gene clusters of the AT-less polyketide synthase (PKS) family of metabolites is the introduction of carbon branches by a gene cassette that contains a β-hydroxy-β-methylglutaryl CoA synthase (HMC) homologue and acyl carrier protein (ACP), ketosynthase (KS) and two crotonase superfamily homologues. In vivo studies of Pseudomonas fluorescens strains in which any of these components have been mutated reveal a common phenotype in which the two major isolable metabolites are the truncated hexaketide mupirocin H and the tetraketide mupiric acid. The structure of the latter has been confirmed by stereoselective synthesis. Mupiric acid is also the major metabolite arising from inactivation of the ketoreductase (KR) domain of module 4 of the modular PKS. A number of other mutations in the tailoring region of the mupirocin gene cluster also result in production of both mupirocin H and mupiric acid. To explain this common phenotype we propose a mechanistic rationale in which both mupirocin H and mupiric acid represent the products of selective and spontaneous release from labile points in the pathway that occur at significant levels when mutations block the pathway either close to or distant from the labile points.
Translated title of the contributionIn vivo Mutational Analysis of the Mupirocin Gene Cluster Reveals Labile Points in the Biosynthetic Pathway: the 'Leaky Hosepipe' Mechanism
Original languageEnglish
Pages (from-to)1500 - 1508
Number of pages9
JournalChemBioChem
Volume9
Issue number9
DOIs
Publication statusPublished - Jun 2008

Bibliographical note

Publisher: Wiley

Fingerprint Dive into the research topics of 'In vivo Mutational Analysis of the Mupirocin Gene Cluster Reveals Labile Points in the Biosynthetic Pathway: the 'Leaky Hosepipe' Mechanism'. Together they form a unique fingerprint.

  • Cite this

    Wu, J., Hothersall, J., Mazzetti, C., O'Connell, Y., Shields, J. A., Rahman, A. S., Cox, R. J., Crosby, J., Simpson, T. J., Thomas, C. M., & Willis, C. L. (2008). In vivo Mutational Analysis of the Mupirocin Gene Cluster Reveals Labile Points in the Biosynthetic Pathway: the 'Leaky Hosepipe' Mechanism. ChemBioChem, 9 (9), 1500 - 1508. https://doi.org/10.1002/cbic.200800085