Details
| Original language | English |
|---|---|
| Pages (from-to) | 825-833 |
| Number of pages | 9 |
| Journal | Chemistry and Biology |
| Volume | 12 |
| Issue number | 7 |
| Publication status | Published - 1 Jul 2005 |
| Externally published | Yes |
Abstract
Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Biochemistry, Genetics and Molecular Biology(all)
- Clinical Biochemistry
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In: Chemistry and Biology, Vol. 12, No. 7, 01.07.2005, p. 825-833.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Shift to Pseudomonic Acid B Production in P. fluorescens NCIMB10586 by Mutation of Mupirocin Tailoring Genes mupO, mupU, mupV, and macpE
AU - Cooper, Sian M.
AU - Laosripaiboon, Wanpen
AU - Rahman, Ayesha S.
AU - Hothersall, Joanne
AU - El-Sayed, A. Kassem
AU - Winfield, Christopher
AU - Crosby, John
AU - Cox, Russell J.
AU - Simpson, Thomas J.
AU - Thomas, Christopher M.
N1 - Funding information: S.M.C. was supported by the School of Biosciences, University of Birmingham. W.L. was supported by a scholarship from the University of Bristol. A.S.R. was supported by a scholarship from the Darwin Trust of Edinburgh. J.H. was supported by Biotechnology and Biological Sciences Research Council grants P15257 and 07071, which also covered the cost of consumables. C.W. was supported by Biotechnology and Biological Sciences Research Council grant 7/B11480. DNA sequencing was performed in the University of Birmingham Functional Genomics Laboratory, funded by BBSRC grant 6/JIF13209. DNA sequence analysis software was provided by Birmingham Medical Research Council Bioinformatics Project (MRC G.4600017 grant for Bioinformatics Infrastructure). The mupirocin used as standard was a gift from GlaxoSmithKline.
PY - 2005/7/1
Y1 - 2005/7/1
N2 - Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.
AB - Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.
UR - http://www.scopus.com/inward/record.url?scp=22544461948&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2005.05.015
DO - 10.1016/j.chembiol.2005.05.015
M3 - Article
C2 - 16039529
AN - SCOPUS:22544461948
VL - 12
SP - 825
EP - 833
JO - Chemistry and Biology
JF - Chemistry and Biology
SN - 1074-5521
IS - 7
ER -