Details
| Original language | English |
|---|---|
| Pages (from-to) | 1500-1508 |
| Number of pages | 9 |
| Journal | CHEMBIOCHEM |
| Volume | 9 |
| Issue number | 9 |
| Publication status | Published - 16 Jun 2008 |
| Externally published | Yes |
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.
Keywords
- Antibiotics, Biosynthesis, Mutagenesis, Natural products, Polyketides
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
- Chemistry(all)
- Organic Chemistry
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In: CHEMBIOCHEM, Vol. 9, No. 9, 16.06.2008, p. 1500-1508.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - In vivo mutational analysis of the mupirocin gene cluster reveals labile points in the biosynthetic pathway
T2 - The "leaky hosepipe" mechanism
AU - Wu, Ji'en
AU - Hothersall, Joanne
AU - Mazzetti, Carlo
AU - O'Connell, Yvonne
AU - Shields, Jennifer A.
AU - Rahman, Ayesha S.
AU - Cox, Russell J.
AU - Crosby, John
AU - Simpson, Thomas J.
AU - Thomas, Christopher M.
AU - Willis, Christine L.
PY - 2008/6/16
Y1 - 2008/6/16
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Biosynthesis
KW - Mutagenesis
KW - Natural products
KW - Polyketides
UR - http://www.scopus.com/inward/record.url?scp=49249099787&partnerID=8YFLogxK
U2 - 10.1002/cbic.200800085
DO - 10.1002/cbic.200800085
M3 - Article
C2 - 18465759
AN - SCOPUS:49249099787
VL - 9
SP - 1500
EP - 1508
JO - CHEMBIOCHEM
JF - CHEMBIOCHEM
SN - 1439-4227
IS - 9
ER -