Stereochemische Uniformität bei marinen Polyetherleitern: Folgerungen für Biosynthese und Struktur des Maitotoxins

Gallimore, Andrew R.; Spencer, Jonathan B.

doi:10.1002/ange.200504284

Cited by 22 publications

(23 citation statements)

References 54 publications

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“…[221][222][223] Die Sequenz wird durch den nucleophilen Angriff einer Hydroxy-Gruppe eines Halbacetals auf eine Carbonyleinheit eingeleitet, die anschließend die benachbarte Epoxy-Gruppe angreift, und Elektronen werden durch die präorganisierte Polyketid-Kette weitergegeben. Die gleiche Route wird wahrscheinlich bei der Biosynthese der Polyether-Leitern, die in marinen Toxinen wie Maitotoxin [226] gefunden werden, verfolgt. Anscheinend ist der stereochemische Verlauf der Epoxidierung einheitlich und bestimmt die absolute Konfiguration der Moleküle.…”

Section: O-heterocyclenunclassified

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: O-heterocyclenunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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“…Despite recent advances, the molecular basis for this exquisite stereospecificity, and the exact sequence of enzymatic steps, remain unclear. Even less is known of the biosynthesis by marine dinoflagellates of notorious polyether toxins such as brevetoxin and maitotoxin,6 easily the most structurally complex and poisonous of polyketide natural products. An added incentive to study terrestrial polyether ionophore biosynthesis is the possibility of using information gleaned from these simpler systems to guide the search for the marine toxin genes 7…”

Section: Introductionmentioning

confidence: 99%

“… Structures of monensin ( 1 ), lasalocid ( 2 ) and iso‐lasalocid ( 3 ). Polyether rings arising from either exo ‐ tet (kinetically favoured) ring closure or endo ‐ tet (disfavoured) ring closure, according to Baldwin's rules,6 are labelled accordingly. …”

Section: Introductionmentioning

confidence: 99%

Analysis of Specific Mutants in the Lasalocid Gene Cluster: Evidence for Enzymatic Catalysis of a Disfavoured Polyether Ring Closure

et al. 2008

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Lasalocid is a highly atypical polyether ionophoric antibiotic, firstly because it contains a type of aromatic ring normally associated with fungal polyketides, and secondly because the formation of its tetrahydropyran ring appears to contravene Baldwin's rules, which predict the kinetically preferred routes for cyclisation reactions in organic chemistry. The lasalocid biosynthetic gene cluster has been cloned from Streptomyces lasaliensis, and the las locus (73,533 bp) was found to contain seven modular polyketide synthase (PKS) genes, including all the activities necessary for the synthesis of the aromatic moiety. Specific deletion from the gene cluster of the flanking lasC gene, which is predicted to encode a flavin-linked epoxidase, abolished production both of lasalocid and of the minor cometabolite iso-lasalocid without leading to accumulation of an identifiable intermediate; this suggests that oxidative cyclisation to form the polyether rings takes place on the PKS before release of the full-length polyketide product. Meanwhile, a mutant in which the adjacent epoxide hydrolase lasB had been deleted produced iso-lasalocid only. Iso-lasalocid differs from lasalocid in the replacement of the tetrahydropyran ring by a tetrohydrofuran ring and represents the kinetically favoured product of cyclisation. The LasB epoxide hydrolase is therefore directly implicated in control of the stereochemical course of polyether ring formation during lasalocid biosynthesis.

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“…It was the Gallimore and Spencer questioning of the maitotoxin C51–C52 stereochemical configuration [9] that prompted us to initiate our investigations in the maitotoxin project. Our first foray into resolving the C51–C52 maitotoxin stereochemical controversy was computational in nature.…”

Section: Synthesis Of Maitotoxin Domainsmentioning

confidence: 99%

“…Fully assigned by 1996, the structure of this impressive molecule laid in the literature undisturbed until 2006 when Gallimore and Spencer noticed an “abnormality” within it that did not conform to their proposed biosynthetic hypothesis (see Figure 2). [9] Based on the previously proposed biosynthesis of brevetoxin B ( 4 , see Figure 3), [10] and invoking polyepoxide cascade openings, this hypothesis required inversion of configuration at C51–C52 (JK ring junction; see Figure 2). It was this cloud of uncertainty cast over the structure of maitotoxin that prompted us to study this molecule.…”

Section: Introductionmentioning

confidence: 99%

Maitotoxin: An Inspiration for Synthesis

Nicolaou

Aversa

2011

Israel Journal of Chemistry

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Maitotoxin holds a special place in the annals of natural products chemistry as the largest and most toxic secondary metabolite known to date. Its fascinating, ladder-like, polyether molecular structure and diverse spectrum of biological activities elicited keen interest from chemists and biologists who recognized its uniqueness and potential as a probe and inspiration for research in chemistry and biology. Synthetic studies in the area benefited from methodologies and strategies that were developed as part of chemical synthesis programs directed toward the total synthesis of some of the less complex members of the polyether marine biotoxin class, of which maitotoxin is the flagship. This account focuses on progress made in the authors’ laboratories in the synthesis of large maitotoxin domains with emphasis on methodology development, strategy design, and structural comparisons of the synthesized molecules with the corresponding regions of the natural product. The article concludes with an overview of maitotoxin’s biological profile and future perspectives.

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Stereochemische Uniformität bei marinen Polyetherleitern: Folgerungen für Biosynthese und Struktur des Maitotoxins

Cited by 22 publications

References 54 publications

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Analysis of Specific Mutants in the Lasalocid Gene Cluster: Evidence for Enzymatic Catalysis of a Disfavoured Polyether Ring Closure

Maitotoxin: An Inspiration for Synthesis

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