Biosynthesis of Pentangular Polyphenols:  Deductions from the Benastatin and Griseorhodin Pathways

Lackner, Gerald; Schenk, Angéla; Xu, Zhongli; Reinhardt, Kathrin; Yunt, Zeynep; Piel, Jörn; Hertweck, Christian

doi:10.1021/ja0718624

Cited by 63 publications

(71 citation statements)

References 33 publications

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“…We found that most gene clusters contain at least one KR gene (Table 1). Previous phylogenetic analysis suggested there are four main classes of type II PKS KRs, which correlate with the regiospecificity of the reduction event: C9, C15, C17, and C19 (24). The four main classes of KRs are distinct at the sequence level, evolved with their clustered KS (SI Appendix, Figs.…”

Section: Resultsmentioning

confidence: 95%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

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

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Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.evolution | polyketide | natural products | gene cluster

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Section: Resultsmentioning

confidence: 95%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

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

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“…3B shows a biogenic proposal for the formation of compounds 3 and 4 from the cyclization and functionalization of a tridecaketide precursor. KS β AZ154, which is used in the biosynthesis of compounds 3 and 4, falls in a clade with KS β genes from functionally characterized minimal PKSs that produce long chain polyketides (>10 acetates) and pathways that proceed through related pentacyclic intermediates (29) (Fig. 3B).…”

Section: Resultsmentioning

confidence: 99%

Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites

Feng

Kallifidas²,

Brady³

2011

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

135

149

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A single gram of soil is predicted to contain thousands of unique bacterial species. The majority of these species remain recalcitrant to standard culture methods, prohibiting their use as sources of unique bioactive small molecules. The cloning and analysis of DNA extracted directly from environmental samples (environmental DNA, eDNA) provides a means of exploring the biosynthetic capacity of natural bacterial populations. Environmental DNA libraries contain large reservoirs of bacterial genetic diversity from which new secondary metabolite gene clusters can be systematically recovered and studied. The identification and heterologous expression of type II polyketide synthase-containing eDNA clones is reported here. Functional analysis of three soil DNA-derived polyketide synthase systems in Streptomyces albus revealed diverse metabolites belonging to well-known, rare, and previously uncharacterized structural families. The first of these systems is predicted to encode the production of the known antibiotic landomycin E. The second was found to encode the production of a metabolite with a previously uncharacterized pentacyclic ring system. The third was found to encode the production of unique KB-3346-5 derivatives, which show activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These results, together with those of other small-moleculedirected metagenomic studies, suggest that culture-independent approaches are capable of accessing biosynthetic diversity that has not yet been extensively explored using culture-based methods. The large-scale functional screening of eDNA clones should be a productive strategy for generating structurally previously uncharacterized chemical entities for use in future drug development efforts. D espite the historical success of bacterial natural products as lead structures for the development of small molecule therapeutics and the continued need for new antimicrobials and chemotherapeutics, large screening programs have deemphasized the use of microbial extracts over the past two decades. The reason most frequently cited for this decline is the persistent rediscovery of known metabolites (1-3). Most environmental bacteria remain recalcitrant to standard culture methods (4-6), and the difficulties associated with growing these organisms prohibit their use as new sources of bioactive small molecules. Although it is not yet possible to easily culture the majority of environmental bacteria, it is possible to extract microbial DNA directly from environmental samples (environmental DNA, eDNA) and to clone this DNA into cultured bacteria where it can be functionally characterized. This general approach has been termed metagenomics (7). The application of metagenomics to the study of bacterial secondary metabolism is particularly appealing in light of the fact that the genes required for the biosynthesis of a natural product are typically clustered on a bacterial chromosome. The heterologous expression of natural product gene clusters ...

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“…Diese haben identische frühe Biosynthesestufen, die zu einer pentangulären Grundstruktur führen (Schema 24). [115] Li und Piel haben den Gencluster identifiziert, der für die Griseorhodin-Biosynthese in einer marinen Streptomyces sp. [116] codiert.…”

Section: Aberrante Cyclisierung Aromatischer Polyketide (Favorskiiase)unclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

Self Cite

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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Biosynthesis of Pentangular Polyphenols: Deductions from the Benastatin and Griseorhodin Pathways

Cited by 63 publications

References 33 publications

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Functional analysis of environmental DNA-derived type II polyketide synthases reveals structurally diverse secondary metabolites

Die biosynthetische Grundlage der Polyketid‐Vielfalt

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