Analysis of Modular-iterative Mixed Biosynthesis of Lankacidin by Heterologous Expression and Gene Fusion

Tatsuno, Satoshi; Arakawa, Kenji; Kinashi, Haruyasu

doi:10.1038/ja.2007.90

Cited by 47 publications

(27 citation statements)

References 23 publications

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“…AurA vom Aureothin-Biosyntheseweg katalysiert zwei Elongations-und b-Ketoprozessierungsrunden, [249] während BorA5 vom Borrelidin-Biosyntheseweg sogar drei Verlängerungszyklen katalysiert. [250] Weitere Beispiele sind die iterativen modularen Polyketid-Synthasen für Neoaureothin (100), Neocarcilin (101), [251] Lankacidin (89) [252,253] und DKxanthen. [254] Interessanterweise kann ein Pikromycin-PKS-Modul iterativ wirken, wenn es aus seiner natürlichen Umgebung herausgenommen wird.…”

Section: "Stottern" Und Programmierte Iterationunclassified

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: "Stottern" Und Programmierte Iterationunclassified

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Hertweck

2009

Angewandte Chemie

205

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“…In regards to the second question, we proposed a hypothesis of modular-iterative mixed polyketide biosynthesis for lankacidin (Arakawa et al, 2005). This hypothesis was supported by the following two pieces of experimental evidence (Tatsuno et al, 2007). Heterologous expression of the lankacidin cluster (lkcA-lkcO) in S. lividans resulted in lankacidinol A production, indicating that the gene cluster is sufficient for the synthesis of the lankacidin skeleton.…”

Section: Physical Characterization Of Scp1mentioning

confidence: 67%

Antibiotic production, linear plasmids and linear chromosomes in Streptomyces

Kinashi¹

2008

Actinomycetologica

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“…As a test for the validation of the LEXAS procedure, we chose S. rochei Sal35, recently isolated from Shennongjia (Eastern Hubei) forest soil. Other S. rochei strains have previously been reported to hold BGCs for the production of streptothricin (30), borrelidin (35), lankacidin (36), and lankamycin (37). PCR primers were designed to detect the homologous BGCs in S. rochei Sal35.…”

Section: Resultsmentioning

confidence: 99%

Functional Genome Mining for Metabolites Encoded by Large Gene Clusters through Heterologous Expression of a Whole-Genome Bacterial Artificial Chromosome Library in Streptomyces spp

Wang

Zhao

et al. 2016

Appl Environ Microbiol

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Genome sequencing projects in the last decade revealed numerous cryptic biosynthetic pathways for unknown secondary metabolites in microbes, revitalizing drug discovery from microbial metabolites by approaches called genome mining. In this work, we developed a heterologous expression and functional screening approach for genome mining from genomic bacterial artificial chromosome (BAC) libraries in Streptomyces spp. We demonstrate mining from a strain of Streptomyces rochei, which is known to produce streptothricins and borrelidin, by expressing its BAC library in the surrogate host Streptomyces lividans SBT5, and screening for antimicrobial activity. In addition to the successful capture of the streptothricin and borrelidin biosynthetic gene clusters, we discovered two novel linear lipopeptides and their corresponding biosynthetic gene cluster, as well as a novel cryptic gene cluster for an unknown antibiotic from S. rochei. This high-throughput functional genome mining approach can be easily applied to other streptomycetes, and it is very suitable for the large-scale screening of genomic BAC libraries for bioactive natural products and the corresponding biosynthetic pathways. IMPORTANCEMicrobial genomes encode numerous cryptic biosynthetic gene clusters for unknown small metabolites with potential biological activities. Several genome mining approaches have been developed to activate and bring these cryptic metabolites to biological tests for future drug discovery. Previous sequence-guided procedures relied on bioinformatic analysis to predict potentially interesting biosynthetic gene clusters. In this study, we describe an efficient approach based on heterologous expression and functional screening of a whole-genome library for the mining of bioactive metabolites from Streptomyces. The usefulness of this function-driven approach was demonstrated by the capture of four large biosynthetic gene clusters for metabolites of various chemical types, including streptothricins, borrelidin, two novel lipopeptides, and one unknown antibiotic from Streptomyces rochei Sal35. The transfer, expression, and screening of the library were all performed in a high-throughput way, so that this approach is scalable and adaptable to industrial automation for next-generation antibiotic discovery. Microbial natural products have been a main source of drugs during the last century due to their diverse structures and bioactivities (1). The natural product drug pipeline seems to have stalled in the last 3 decades, even though recent Streptomyces genome sequencing projects have uncovered multiple biosynthetic gene clusters (BGCs) for undiscovered natural products (secondary metabolites), far exceeding the number of known metabolites (2-4). However, those BGCs are usually cryptic under laboratory conditions, producing very little or no corresponding secondary metabolites, which are needed for biological testing (5, 6).Different approaches have been developed to activate the cryptic BGCs for coelichelin, clostrubin, stambomycin, and...

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Analysis of Modular-iterative Mixed Biosynthesis of Lankacidin by Heterologous Expression and Gene Fusion

Cited by 47 publications

References 23 publications

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Die biosynthetische Grundlage der Polyketid‐Vielfalt

Antibiotic production, linear plasmids and linear chromosomes in Streptomyces

Functional Genome Mining for Metabolites Encoded by Large Gene Clusters through Heterologous Expression of a Whole-Genome Bacterial Artificial Chromosome Library in Streptomyces spp

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