Characterization of the mupirocin biosynthesis gene cluster from Pseudomonas fluorescens NCIMB 10586.
The polyketide antibiotic mupirocin (pseudomonic acid) produced by Pseudomonas fluorescens NCIMB 10586 competitively inhibits bacterial isoleucyl-tRNA synthase and is useful in controlling Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus. The 74 kb mupirocin biosynthesis cluster has been sequenced, and putative enzymatic functions of many of the open reading frames (ORFs) have been identified. The mupirocin cluster is a combination of six larger ORFs (mmpA-F), containing several domains resembling the multifunctional proteins of polyketide synthase and fatty acid synthase type I systems, and individual genes (mupA-X and macpA-E), some of which show similarity to type II systems (mupB, mupD, mupG, and mupS). Gene knockout experiments demonstrated the importance of regions in mupirocin production, and complementation of the disrupted gene confirmed that the phenotypes were not due to polar effects. A model for mupirocin biosynthesis is presented based on the sequence and biochemical evidence.
El-Sayed
A Kassem
AK
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Hothersall
Joanne
J
Cooper
Sian M
SM
Stephens
Elton
E
Simpson
Thomas J
TJ
Thomas
Christopher M
CM
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000235:genetics; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005798:Genes, Bacterial; D006836:Hydro-Lyases / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D008956:Models, Chemical; D008969:Molecular Sequence Data; D005810:Multigene Family; D016712:Mupirocin / Q000096:biosynthesis*; D016366:Open Reading Frames; D011551:Pseudomonas fluorescens / Q000235:genetics* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D016712:Mupirocin; D015094:3-Hydroxyacyl CoA Dehydrogenases; D008780:Methyltransferases; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D006836:Hydro-Lyases