Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescens

Martin, Fionna M.; Simpson, Thomas J.

doi:10.1039/p19890000207

Cited by 26 publications

(24 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we have subsequently shown that MupC must normally act after MupO, U, V and other proteins responsible for formation of the THP ring, [18] reducing the 8,9-alkene of an a,b-unsaturated ketone located between C9 and C7. However, isolation of mupirocin H (12) and mupiric acid (14), which must be formed from pre-THP intermediates, is consistent with the original proposed in trans action of MupC on PKS-bound tetraketide 3. MupC might thus be able to manifest activity on different substrates.…”

Section: Possible Role Of Mupc In 89-alkene Reduction To Produce Mupsupporting

confidence: 79%

See 1 more Smart Citation

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

Hothersall

Mazzetti

et al. 2008

ChemBioChem

Self Cite

View full text Add to dashboard Cite

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 beta-hydroxy-beta-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.

show abstract

Section: Possible Role Of Mupc In 89-alkene Reduction To Produce Mupsupporting

confidence: 79%

“…Pseudomonic acid A (1, R= H), [13] consisting of monic acid (MA) esterified [14] by 9-hydroxynonanoic acid (Scheme 1), is the major component of mupirocin. The thiomarinols isolated from the marine bacterium Alteromonas rava have very similar structures and are probably the products of closely related genes.…”

Section: Introductionmentioning

confidence: 99%

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

Hothersall

Mazzetti

et al. 2008

ChemBioChem

Self Cite

View full text Add to dashboard Cite

show abstract

“…Subsequent decarboxylation and dehydration would then lead to IPP by the normal series of reactions. In the second route, the HMG is released from its bound state and, after decarboxylation and dehydration, is converted into either 3-methylbut-2-enoic acid or 3-methylbut-3-enoic acid (Martin & Simpson, 1989). These acids are then converted into either IPP or dimethylallyl pyrophosphate by reduction of the acid group to an alcohol and by the subsequent formation ofthe pyrophosphate ester.…”

Section: Discussionmentioning

confidence: 99%

Early steps of isoprenoid biosynthesis in Escherichia coli

Zhou

White

1991

Biochemical Journal

View full text Add to dashboard Cite

The incorporation of 2H- and 13C-labelled precursors into ubiquinone-8 (Uq-8) by strains of Escherichia coli was measured in order to define the pathway for the early steps in the biosynthesis of isoprenoids in these eubacteria. Cells grown with DL-[methyl-2H6]valine were found to label both the alpha-oxoisovaleric (‘alpha-ketoisovaleric’) acid alpha-oxoisohexanoic (‘alpha-ketoisocaproic’) acid, but not the Uq-8. Since these acids are required for the biosynthesis of isoprenoids by the acetolactate pathway, the operation of this pathway in the biosynthesis of Uq-8 is excluded. Cells grown with [1,2-13C2]acetate and non-labelled glucose readily incorporated 13C2 units into fatty acids, but failed to incorporate any label into the Uq-8. Cells grown with [U-13C6]glucose and non-labelled acetate, however, were found to label both the fatty acids and the Uq-8. Oxidative cleavage with periodate/permanganate of the Uq-8 isolated from cells grown with U-13C6-labelled glucose produced laevulinic acid, which was shown to be derived from two C2 units and one C1 unit of the labelled glucose by mass-spectral analysis of the 4,5-dihydro-6-methyl-2-phenylpyridazin-3(2H)-one derivative. The results of this work indicate that the C-2 and C-3 carbon unit of pyruvate, not acetyl-CoA, is the precursor to isopentenyl pyrophosphate (IPP) in these cells; however, the labelling pattern observed is consistent with the established acetoacetate pathway of isoprenoid biosynthesis. These data, coupled with the observed lack of inhibition of the growth of E. coli by mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-CoA, can be best rationalized by the biosynthesis of IPP occurring in E. coli through a series of bound intermediates.

show abstract

“…However, the CI2, C,and C, units have been identified as products of separate A. WHATLING a n d OTHERS pathways that are subsequently assembled together (Martin & Simpson, 1989). An early suggestion that the c, unit and 9-hydroxynonanoic acid are derived from hydroxymethylglutaryl-CoA (HMG-CoA ; Feline et al, 1977) has been disproved (Martin & Simpson, 1989). Instead, the entire molecule is derived from acetate, with the exception of C-16 and C-17, which are derived from the methyl of methionine (Feline etal., 1977).…”

Section: Introductionmentioning

confidence: 99%

Identification of a 60 kb region of the chromosome of Pseudomonas fluorescens NCIB 10586 required for the biosynthesis of pseudomonic acid (mupirocin)

et al. 1995

View full text Add to dashboard Cite

Pseudomonic acid (mupirocin) produced by Pseudomonas fluorescens is a polyketide antibiotic which blocks isoleucyl-tRNA synthetase. Knowledge of the biosynthetic pathways leading to pseudomonic acid production may help in engineering related antibiotics with other useful properties. To help define these pathways, we have isolated 13 non-producing mutants using Tn5 and Tn1725 mutagenesis. Seven of the Tn5 insertions mapped within a 55 kb region. The remaining insertions, and one gene encoding resistance to pseudomonic acid, mapped at separate locations. DNA that overlapped the seven clustered Tn5 insertions was isolated on a series of clones, extending over a region in excess of 60 kb. Non-producing mutants generated via gene disruption suggest that the biosynthetic cluster extends throughout this region.

show abstract

Biosynthetic studies on pseudomonic acid (mupirocin), a novel antibiotic metabolite of Pseudomonas fluorescens

Cited by 26 publications

References 0 publications

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

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

Early steps of isoprenoid biosynthesis in Escherichia coli

Identification of a 60 kb region of the chromosome of Pseudomonas fluorescens NCIB 10586 required for the biosynthesis of pseudomonic acid (mupirocin)

Contact Info

Product

Resources

About