New Rapamycin Derivatives by Precursor‐Directed Biosynthesis

Lowden, Philip A.S; Böhm, Günter A.; Metcalfe, Su; Staunton, James; Leadlay, Peter F.

doi:10.1002/cbic.200300758

Cited by 47 publications

(47 citation statements)

References 29 publications

(10 reference statements)

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“…[137] Eines der wichtigsten Beispiele ist die manipulierte Biosynthese zum Avermectin-Derivat Doramectin, das klinische Anwendung als sehr wirksames Wurmmittel findet. [138] Weitere erfolgreiche Mutasynthesen lieferten neue biologisch aktive Analoga von Aureothin, [139] Rapamycin, [140,141] Borrelidin, [142] Myxalamid [143] und Ansamitocin.…”

Section: Lademechanismen Und Seltene Startereinheitenunclassified

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: Lademechanismen Und Seltene Startereinheitenunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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“…Such analogs have been created by using synthetic methods (2,16), semisynthetic methods (21), and precursor feeding (9,10,12,18), and there have been substantial efforts to achieve this goal by manipulation of the biosynthetic gene cluster (4,6,7,9). In our efforts to generate novel rapamycin analogs, we have evaluated feeding S. hygroscopicus with alternative rapamycin precursor molecules (precursor-directed biosynthesis).…”

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confidence: 99%

Production of Novel Rapamycin Analogs by Precursor-Directed Biosynthesis

Ritacco

Graziani

Summers

et al. 2005

Appl Environ Microbiol

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The natural product rapamycin, produced during fermentation by Streptomyces hygroscopicus, is known for its potent antifungal, immunosuppressive, and anticancer activities. During rapamycin biosynthesis, the amino acid L-pipecolate is incorporated into the rapamycin molecule. We investigated the use of precursor-directed biosynthesis to create new rapamycin analogs by substitution of unusual L-pipecolate analogs in place of the normal amino acid. Our results suggest that the L-pipecolate analog (؎)-nipecotic acid inhibits the biosynthesis of L-pipecolate, thereby limiting the availability of this molecule for rapamycin biosynthesis. We used (؎)-nipecotic acid in our precursor-directed biosynthesis studies to reduce L-pipecolate availability and thereby enhance the incorporation of other pipecolate analogs into the rapamycin molecule. We describe here the use of this method for production of two new sulfur-containing rapamycin analogs, 20-thiarapamycin and 15-deoxo-19-sulfoxylrapamycin, and report measurement of their binding to FKBP12. Rapamycin (Fig.

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“…For example, the Biotica group (Cambridge, UK) revealed various positive regulatory elements in rapamycin biosynthesis, 23 the Wyeth group (Madison, NJ, USA) modified the pipecolate ring of rapamycin and Leadlay and coworkers 24 synthesized several rapamycin analogs with modifications to the cyclohexyl moiety through genetic engineering and mutasynthesis. Recently, Graziani 25 provided a review article on the advances in the field of rapamycin biosynthesis and neuroprotective activity of rapamycin analogs.…”

Section: Figurementioning

confidence: 99%

“…When carboxylic acids such as cyclohexanecarboxylic acid, cyclohex-1-ene-carboxylic acid and cycloheptanecarboxylic acid in place of the natural starter unit DHCHC were fed to cultures of an engineered strain of S. hygroscopicus MG2-10 in which rapKIJMNOQL is deleted from the rapamycin biosynthetic gene cluster, the resulting mutants gave pre-rapamycin analogs. 70 This study was based on the precursordirected biosynthesis carried out by Lowden et al 24 in which the feeding of alternative starter units, such as cyclohexanecarboxylic acid, cyclohex-1-ene-carboxylic acid and cycloheptanecarboxylic acid, to the fermentation of rapamycin-producing S. hygroscopicus led to the production of new rapamycin derivatives (compounds 14, 15 and 16; Figure 1). …”

Section: Mutagenesis and Mutasynthesismentioning

confidence: 99%

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

et al. 2010

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Rapamycin and its analogs are clinically important macrolide compounds produced by Streptomyces hygroscopicus. They exhibit antifungal, immunosuppressive, antitumor, neuroprotective and antiaging activities. The core macrolactone ring of rapamycin is biosynthesized by hybrid type I modular polyketide synthase (PKS)/nonribosomal peptide synthetase systems primed with 4,5-dihydrocyclohex-1-ene-carboxylic acid. The linear polyketide chain is condensed with pipecolate by peptide synthetase, followed by cyclization to form the macrolide ring and modified by a series of post-PKS tailoring steps. The aim of this review was to outline past and recent advances in the biosynthesis and regulation of rapamycin, with an emphasis on the distinguished contributions of Professor Demain to the study of rapamycin. In addition, this article describes the biological activities as well as mechanism of action of rapamycin and its derivatives. Recent attempts to improve the productivity of rapamycin and generate diverse rapamycin analogs through mutasynthesis and mutagenesis are also introduced, along with some future perspectives.

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New Rapamycin Derivatives by Precursor‐Directed Biosynthesis

Cited by 47 publications

References 29 publications

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Production of Novel Rapamycin Analogs by Precursor-Directed Biosynthesis

Biosynthesis of rapamycin and its regulation: past achievements and recent progress

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