Synthetic Strategy of Nonreducing Iterative Polyketide Synthases and the Origin of the Classical “Starter‐Unit Effect”

Crawford, Jason M.; Vagstad, Anna L.; Whitworth, Karen; Ehrlich, Kenneth C.; Townsend, Craig A.

doi:10.1002/cbic.200700702

Cited by 42 publications

(44 citation statements)

References 55 publications

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“…Interestingly, the conserved Gln that has been proposed to stabilize the oxyanion hole during acyl transfer (46,53) is replaced by V14 in AtCURS2 and also in its uncharacterized P. tritici-repentis ortholog EDU47223. The substrate of the transacylation reaction catalyzed by the AtCURS2 SAT domain (14,53,54) is predicted to be 7(S)-hydroxyoct-2(E)-enoic acid, assembled on the AtCURS1 hrPKS. This is the shortest starter unit among the characterized RAL/DAL systems, as this is a tetraketide as opposed to the pentaketide for radicicol and the hexaketides for zearalenone and hypothemycin biosynthesis (26,27).…”

Section: Isolation Of the Dehydrocurvularin Biosynthetic Locusmentioning

confidence: 99%

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Espinosa-Artiles

Schubert

et al. 2013

Appl Environ Microbiol

115

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d 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta-or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.

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Section: Isolation Of the Dehydrocurvularin Biosynthetic Locusmentioning

confidence: 99%

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Espinosa-Artiles

Schubert

et al. 2013

Appl Environ Microbiol

115

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“…A decade of failed experiments in yeast and fungal expression systems was easily overcome in E. coli to give catalytically autonomous parts that reassembled in solution to faithfully recapitulate native synthetic function. First, the unusually long N -terminal domain was found to be a “starter unit transacylase” (SAT) domain and the origin of the classically observed “starter unit effect,” 42, 43 that ordinarily brings acetyl CoA onto the PKS to initiate fungal polyketide elongation, or, as in the case of PksA, an allied specialized FAS transfers a hexanoyl unit to the SAT. 44 It is now recognized that other PKSs can load the SAT of an NR-PKS as well.…”

Section: Rediscovery Of Non-reducing Pkssmentioning

confidence: 99%

Aflatoxin and deconstruction of type I, iterative polyketide synthase function

Townsend

2014

Nat. Prod. Rep.

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In this viewpoint highlights are drawn from a deep analysis of the multifaceted problem of aflatoxin biosynthesis, one of the most highly rearranged polyketide natural products known. Fundamental chemical insights have emerged into how cytochrome P450-mediated skeletal rearrangements occur through probable cationic intermediates and oxidative dearomatizations, which are applicable more widely in natural product catabolism. So to where current experimental methods have failed in our hands, bioinformatic tools and fresh experimental strategies have been developed to identify linker regions in large, polydomain proteins and guide the dissection and reassembly of their component parts.It has been possible to deduce individual catalytic roles, how overall synthesis is coordinated and how these enzymes can be re-engineered in a rational manner to prepare non-natural products. These insights and innovations were often not planned or anticipated, but sprung from the inability to answer fundamental questions. Advances in science can take place by chance favoring the prepared mind, other times by refusing to give up and devising new solutions to address hard questions. Both ways forward played important roles in the investigation of aflatoxin biosynthesis. For these contributions I am pleased to share this special issue of NPR with John Vederas and Tom Simpson, who have been leaders in this field for the last third of a century.

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“…[46,48] Die Beladung der iterativen Typ-I-PKS in Pilzen war ein Rätsel, bis Townsend et al vor kurzem Pilz-PKS-Domänen systematisch analysierten und eine Starter-Acyltransferase-(SAT)-Domäne identifizierten. [49,50] Diese N-terminale Domäne ist substratspezifisch und führt das Startermolekül der PKS zu, wie für die Hexanoat-initiierte Norsolorinsäu-re(9)-Synthase (NSAS) gezeigt wurde (Schema 6). Ein alternativer Beladungsmechanismus wurde bei der Biosynthese von Zearalenon (10), einem Mycotoxin aus Gibberella zeae, das in Tieren das hyperöstrogene Syndrom hervorruft, beobachtet.…”

Section: Polyphenol-diversifizierung Durch Nichtacetylstartereinheitenunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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Molekulares Lego: Polyketide bilden eine äußerst vielfältige Gruppe von Naturstoffen mit faszinierenden Kohlenstoffgerüsten (siehe Beispiele), die aus einfachen Acyl‐Bausteinen synthetisiert werden. Das Zusammenspiel von Chemie, Biochemie und Genetik lieferte wichtige Einblicke in die Programmierung des Polyketid‐Aufbaus und die beteiligten, komplexen Enzymsysteme. Dieser Aufsatz behandelt aktuelle Entwicklungen auf diesem Forschungsgebiet.magnified imagePolyketide bilden eine der größten Naturstoffklassen. Viele dieser Verbindungen – oder Derivate davon – sind wichtige Therapeutika, aber viele sind auch berüchtigte, Lebensmittel verderbende Toxine oder Virulenzfaktoren. Besonders bemerkenswert ist, dass sich die Verbindungen dieser heterogenen Gruppe, zu denen Polyether, Polyene, Polyphenole, Makrolide und Endiine gehören, hauptsächlich von einem der einfachsten natürlichen Bausteine ableiten: Essigsäure. Chemische, genetische und biochemische Untersuchungen haben Aufschluss über die Biosyntheseprogramme gegeben, die zur enormen Strukturvielfalt von Polyketiden führen. Dieser Aufsatz behandelt kürzlich aufgeklärte Biosynthesemechanismen, nach denen höchst unterschiedliche und komplexe Moleküle synthetisiert werden.

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Synthetic Strategy of Nonreducing Iterative Polyketide Synthases and the Origin of the Classical “Starter‐Unit Effect”

Cited by 42 publications

References 55 publications

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Aflatoxin and deconstruction of type I, iterative polyketide synthase function

Die biosynthetische Grundlage der Polyketid‐Vielfalt

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