Authentic Heterologous Expression of the Tenellin Iterative Polyketide Synthase Nonribosomal Peptide Synthetase Requires Coexpression with an Enoyl Reductase

Halo, Laura M.; Marshall, James W.; Yakasai, Ahmed A.; Song, Zhiyong; Butts, Craig P.; Crump, Matthew P.; Heneghan, Mary N.; Bailey, Andy M.; Simpson, Thomas J.; Lazarus, Colin M.; Cox, Russell J.

doi:10.1002/cbic.200700390

Cited by 126 publications

(152 citation statements)

References 45 publications

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“…These eukaryal hybrid enzymes function iteratively in the PKS portion of the enzyme and noniteratively in the NRPS subunits (24). The fungal enzymes display a catalytic domain arrangement with clear similarity to that of FtdB (Fig.…”

Section: Resultsmentioning

confidence: 99%

Common biosynthetic origins for polycyclic tetramate macrolactams from phylogenetically diverse bacteria

Blodgett

Cao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

188

270

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A combination of small molecule chemistry, biosynthetic analysis, and genome mining has revealed the unexpected conservation of polycyclic tetramate macrolactam biosynthetic loci in diverse bacteria. Initially our chemical analysis of a Streptomyces strain associated with the southern pine beetle led to the discovery of frontalamides A and B, two previously undescribed members of this antibiotic family. Genome analyses and genetic manipulation of the producing organism led to the identification of the frontalamide biosynthetic gene cluster and several biosynthetic intermediates. The biosynthetic locus for the frontalamides’ mixed polyketide/amino acid structure encodes a hybrid polyketide synthase nonribosomal peptide synthetase (PKS-NRPS), which resembles iterative enzymes known in fungi. No such mixed iterative PKS-NRPS enzymes have been characterized in bacteria. Genome-mining efforts revealed strikingly conserved frontalamide-like biosynthetic clusters in the genomes of phylogenetically diverse bacteria ranging from proteobacteria to actinomycetes. Screens for environmental actinomycete isolates carrying frontalamide-like biosynthetic loci led to the isolation of a number of positive strains, the majority of which produced candidate frontalamide-like compounds under suitable growth conditions. These results establish the prevalence of frontalamide-like gene clusters in diverse bacterial types, with medicinally important Streptomyces species being particularly enriched.

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Section: Resultsmentioning

confidence: 99%

Common biosynthetic origins for polycyclic tetramate macrolactams from phylogenetically diverse bacteria

Blodgett

Cao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

188

270

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“…In contrast, genetic analyses of the biosynthetic pathway of the 2-pyridone tenellin revealed that this compound does not appear to contribute to B. bassiana virulence (40,41). This system also has been exploited for novel compound discovery, with expression of the tenellin nonribosomal peptide synthase in Aspergillus oryzae leading to the production of several new compounds and the use of chemical epigenetic modifiers in B. bassiana altering the selectivity of tenellin polyketide synthase to produce different products (42,43).…”

Section: Discussionmentioning

confidence: 99%

Regulatory cascade and biological activity of Beauveria bassiana oosporein that limits bacterial growth after host death

Fan

Liu

Keyhani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

119

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The regulatory network and biological functions of the fungal secondary metabolite oosporein have remained obscure. Beauveria bassiana has evolved the ability to parasitize insects and outcompete microbial challengers for assimilation of host nutrients. A novel zinc finger transcription factor, BbSmr1 (B. bassiana secondary metabolite regulator 1), was identified in a screen for oosporein overproduction. Deletion of Bbsmr1 resulted in up-regulation of the oosporein biosynthetic gene cluster (OpS genes) and constitutive oosporein production. Oosporein production was abolished in double mutants of Bbsmr1 and a second transcription factor, OpS3, within the oosporein gene cluster (ΔBbsmr1ΔOpS3), indicating that BbSmr1 acts as a negative regulator of OpS3 expression. Real-time quantitative PCR and a GFP promoter fusion construct of OpS1, the oosporein polyketide synthase, indicated that OpS1 is expressed mainly in insect cadavers at 24-48 h after death. Bacterial colony analysis in B. bassiana-infected insect hosts revealed increasing counts until host death, with a dramatic decrease (∼90%) after death that correlated with oosporein production. In vitro studies verified the inhibitory activity of oosporein against bacteria derived from insect cadavers. These results suggest that oosporein acts as an antimicrobial compound to limit microbial competition on B. bassiana-killed hosts, allowing the fungus to maximally use host nutrients to grow and sporulate on infected cadavers.Beauveria bassiana | oosporein | biological role | transcription factor | fungal-bacterial competition

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“…Selective processing during two successive iterations of polyketide chain extension is a known feature in highly reducing fully iterative polyketide synthases 29, 30, 31. In the LovB PKS, for example, which synthesizes the nonaketide core of the cholesterol‐lowering compound lovastatin using a single PKS module, an integral methyltransferase domain selectively methylates the β‐ketothioester formed after three rounds of chain extension 29.…”

mentioning

confidence: 99%

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

Zhai

Liu

et al. 2017

Angew Chem Int Ed

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Detailed analysis of the modular Type I polyketide synthase (PKS) involved in the biosynthesis of the marginolactone azalomycin F in mangrove Streptomyces sp. 211726 has shown that only nineteen extension modules are required to accomplish twenty cycles of polyketide chain elongation. Analysis of the products of a PKS mutant specifically inactivated in the dehydratase domain of extension‐module 1 showed that this module catalyzes two successive elongations with different outcomes. Strikingly, the enoylreductase domain of this module can apparently be “toggled” off and on : it functions in only the second of these two cycles. This novel mechanism expands our understanding of PKS assembly‐line catalysis and may explain examples of apparent non‐colinearity in other modular PKS systems.

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Authentic Heterologous Expression of the Tenellin Iterative Polyketide Synthase Nonribosomal Peptide Synthetase Requires Coexpression with an Enoyl Reductase

Cited by 126 publications

References 45 publications

Common biosynthetic origins for polycyclic tetramate macrolactams from phylogenetically diverse bacteria

Common biosynthetic origins for polycyclic tetramate macrolactams from phylogenetically diverse bacteria

Regulatory cascade and biological activity of Beauveria bassiana oosporein that limits bacterial growth after host death

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

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