Different polyketide folding modes converge to an identical molecular architecture

Bringmann, Gerhard; Noll, Torsten F; Gulder, Tobias A. M.; Grüne, Matthias; Dreyer, Michael; Wilde, Christopher; Pankewitz, Florian; Hilker, Monika; Payne, Gail; Jones, Amanda; Goodfellow, Michael; Fiedler, Hans‐Peter

doi:10.1038/nchembio805

Cited by 63 publications

(51 citation statements)

References 23 publications

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“…In Eukaryoten (Pilzen, höheren Pflanzen und Insekten) wird Chrysophanol über den Faltungsmodus F (für "Fungi") gebildet; in Actinomyceten verläuft die Cyclisierung dagegen nach dem Modus S (für Streptomyces; Schema 9). [69] Diese vergleichenden Biosynthesestudien belegen, dass bei der Polyketid-Bildung mehr als eine Faltungsweise eine Rolle spielen kann, die regulierenden Enzymfaktoren für die Cyclisierung nach dem F-oder S-Modus bleiben allerdings noch aufzuklären.…”

Section: Divergente Polyketid-faltungsweisen In Pflanzen Pilzen Und unclassified

“…ascomyceticus verantwortlich ist. [147] Andere komplexe Polyketide, die (obwohl andere Verlänge-rungseinheiten vorhanden sind) aus eMCoA-Einheiten bestehen, sind Tylosin, Concanamycin (70) und Kirromycin (69). Das letzte Beispiel ist besonders interessant, da hier die MCoA-, mMCoA-und eMCoA-Verlängerungen durch eigenständige trans-AT-Einheiten ausgewählt werden, die mit den passenden Modulen der PKS wechselwirken müssen.…”

Section: Alternative Verlängerungseinheiten Und Andere Bausteineunclassified

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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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Section: Divergente Polyketid-faltungsweisen In Pflanzen Pilzen Und unclassified

Section: Alternative Verlängerungseinheiten Und Andere Bausteineunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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“…The commonly observed C6-C11 F-mode cyclization is exemplified by the model product emodin and related compounds (25)(26)(27)(28) (Fig. 1B).…”

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Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Tang

2010

Journal of Biological Chemistry

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The fungal iterative nonreducing polyketide synthases (NRPKSs) synthesize aromatic polyketides, many of which have important biological activities. The product template domains (PT) embedded in the multidomain NRPKSs mediate the regioselective cyclization of the highly reactive polyketide backbones and dictate the final structures of the products. Understanding the sequence-activity relationships of different PT domains is therefore an important step toward the prediction of polyketide structures from NRPKS sequences and can enable the genome mining of hundreds of cryptic NRPKSs uncovered via genome sequencing. In this work, we first performed phylogenetic analysis of PT domains from NRPKSs of known functions and showed that the PT domains can be classified into five groups, with each group corresponding to a unique product size or cyclization regioselectivity. Group V contains the formerly unverified PT domains that were identified as C6-C11 aldol cyclases. The regioselectivity of PTs from this group were verified by product-based assays using the PT domain excised from the asperthecin AptA NRPKS. When combined with dissociated PKS4 minimal PKS, or replaced the endogenous PKS4 C2-C7 PT domain in a hybrid NRPKS, AptA-PT directed the C6-C11 cyclization of the nonaketide backbone to yield a tetracyclic pyranoanthraquinone 4. Extensive NMR analysis verified that the backbone of 4 was indeed cyclized with the expected regioselectivity. The PT phylogenetic analysis was then expanded to include ϳ100 PT sequences from unverified NRPKSs. Using the assays developed for AptA-PT, the regioselectivities of additional PT domains were investigated and matched to those predicted by the phylogenetic classifications.

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“…We have recently demonstrated that full-length fungal megasynthases can be expressed and reconstituted in E. coli, hence making this family an attractive machinery for E. coli-based biosynthesis of bacterial aromatic polyketides (13). However, despite the analogous iterative Claisen-like condensations catalyzed by two families of PKSs during chain elongation (10), cyclization modes of the poly-␤-ketone backbones are drastically different (14,15) (Fig. 1).…”

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Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli

Zhang

Tang

2008

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

106

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Bacterial aromatic polyketides are important therapeutic compounds including front line antibiotics and anticancer drugs. It is one of the last remaining major classes of natural products of which the biosynthesis has not been reconstituted in the genetically superior host Escherichia coli. Here, we demonstrate the engineered biosynthesis of bacterial aromatic polyketides in E. coli by using a dissected and reassembled fungal polyketide synthase (PKS). The minimal PKS of the megasynthase PKS4 from Gibberella fujikuroi was extracted by using two approaches. The first approach yielded a stand-alone Ketosynthase (KS)malonyl-CoA:ACP transferase (MAT) didomain and an acyl-carrier protein (ACP) domain, whereas the second approach yielded a compact PKS (PKSWJ) that consists of KS, MAT, and ACP on a single polypeptide. Both minimal PKSs produced nonfungal polyketides cyclized via different regioselectivity, whereas the fungal-specific C2-C7 cyclization mode was not observed. The kinetic properties of the two minimal PKSs were characterized to confirm both PKSs can synthesize polyketides with similar efficiency as the parent PKS4 megasynthase. Both minimal PKSs interacted effectively with exogenous polyketide cyclases as demonstrated by the synthesis of predominantly PK8 3 or NonaSEK4 6 in the presence of a C9-C14 or a C7-C12 cyclase, respectively. When PKSWJ and downstream tailoring enzymes were expressed in E. coli, the expected nonaketide anthraquinone SEK26 was recovered in good titer. High-cell density fermentation was performed to demonstrate the scale-up potential of the in vivo platform for the biosynthesis of bacterial polyketides. Using engineered fungal PKSs can therefore be a general approach toward the heterologous biosynthesis of bacterial aromatic polyketides in E. coli.cyclase ͉ ketosynthase ͉ megasynthase

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Different polyketide folding modes converge to an identical molecular architecture

Cited by 63 publications

References 23 publications

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli

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