Biosynthesis of the Enediyne Antitumor Antibiotic C-1027

Liu, Wen; Christenson, Steven D.; Standage, Scott; Shen, Ben

doi:10.1126/science.1072110

Cited by 275 publications

(423 citation statements)

References 24 publications

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“…6 Quite interestingly, a strain of S. globisporus was shown to produce a 1,4-benzoxazine-type compound similar to that of strain NTK 935. 7,8 Screening, fermentation and isolation Compound 1 was produced by strain NTK 935 in shake-flask cultures in various complex media as monitored by HPLC-diode array analysis. The compound represented a dominant peak in the extracted culture filtrates at a retention time of 7.4 min (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…13 The 1,4-benzoxazine chromophore was described as a building block of the antitumor enediyne antibiotic C-1027 produced by Streptomyces globisporus. 7,8 Nevertheless, the majority of benzoxazine compounds described in the literature are of a synthetic nature, showing manifold biological activities, for example, histidine kinase inhibitors as potential antimicrobial agents. 14 Inhibition of GSK-3b, a key regulator of numerous signaling pathways, has not been reported from other benzoxazine compounds and benzoxacystol (1) is the first reported to exert this activity.…”

Section: Discussionmentioning

confidence: 99%

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Benzoxacystol, a benzoxazine-type enzyme inhibitor from the deep-sea strain Streptomyces sp. NTK 935

et al. 2011

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Benzoxacystol, a new 1,4-benzoxazine-type metabolite, was produced by strain NTK 935, a marine member of the Streptomyces griseus 16S rRNA clade, isolated from deep-sea sediment collected from the Canary Basin. The structure of benzoxacystol was determined by mass spectrometry, NMR experiments and X-ray analysis. The compound showed an inhibitory activity against the enzyme glycogen synthase kinase 3b and a weak antiproliferative activity against mouse fibroblast cells. Keywords: 1,4-benzoxazin-3-one; glycogen synthase kinase 3b; marine Streptomyces INTRODUCTION Actinomycetes from marine sediments collected at various sites in the Atlantic and Pacific Oceans were screened by HPLC-diode array analysis for the production of novel secondary metabolites. Strain NTK 935 was isolated from the same deep-sea sediment core as Streptomyces sp. NTK 937, which we reported recently to produce caboxamycin, a novel antibiotic with a benzoxazole scaffold. 2 Extracts of strain NTK 935 contained a metabolite having an unusual UV-vis spectrum, which was not identified by means of our in-house developed HPLC database. 3 HPLC-ESI-MS analysis revealed a molecular mass of 380, which was-together with UV-vis data-not in accordance with other natural products available in the DNP database. 4 Therefore, strain NTK 935 was selected for fermentation studies, isolation and characterization of the unusual metabolite; this resulted in the identification of the novel 1,4-benzoxazine structure shown in Figure 1.This study describes the taxonomy of the producing strain, fermentation and isolation, structural elucidation and biological activity of the new benzoxazine-type metabolite, which was named benzoxacystol.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Benzoxacystol, a benzoxazine-type enzyme inhibitor from the deep-sea strain Streptomyces sp. NTK 935

et al. 2011

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“…Phylogenetic analysis of the 5 hydroxylases (OXRC) present in loci A and B indicated that four of them are closely related to each other, namely ORF 1 in locus A to ORF 8 in locus B and ORF 2 in locus A to ORF 15 in locus B. All four ORFs are related to enzymes that hydroxylate 6-membered ring structures such as sgcD3 in the C-1027 gene cluster that hydroxylates carbon 5 of the 3-hydroxy-anthranilic acid component [12]. A possible function for these ORFs would be hydroxylation, most likely at position 3 of the pyran-2-one moiety, the 6-membered ring intermediate structure, formed through the action of the terminal thioesterase.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Identification of Three New 5-Alkenyl-3,3(2H)-furanones from Two Streptomyces species using a Genomic Screening Approach

et al. 2006

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Analyses of biosynthetic gene clusters derived from Streptomyces aculeolatus NRRL 18422 and Streptomyces sp. Eco86 indicated that both microorganisms have similar type I polyketide synthase (PKS) gene clusters with relatively few genes encoding post-PKS elaborative enzymes. However both gene clusters included a sequence coding for a relatively uncommon oxidative enzyme related to Baeyer-Villiger, flavin-type monooxygenases. Screening of culture extracts for compounds with the predicted physicochemical properties of the end products from these loci, led to the isolation of three 5-alkenyl-3,3(2H)-furanones, one (E-837, 1) from the former and two (E-492, 2, E-975, 3) from the latter strain. The structures, confirmed by spectral analyses including MS, and 1D and 2D NMR experiments, were in accord with those predicted by genomic analyses. Baeyer-Villiger type oxidation is postulated to be involved in the formation of the furanone moieties in these molecules. All three new compounds were tested for their electron transport inhibitory activities. They had IC 50 values of 1ϳ4 mg/ml against Ascaris suum NADH-fumarate reductase and 1ϳ12 mg/ml against bovine heart NADH oxidase.Keywords Streptomyces aculeolatus, Streptomyces sp., E-837, E-492, E-975, Baeyer-Villiger monooxygenase IntroductionNatural products play an important role in drug discovery and have been used for the treatment of various diseases for decades. They constitute a leading source of novel molecules for the development of new drug candidates to treat life threatening infections and other human disorders [1]. To identify such potential drug candidates from nature, different methods have been developed and routinely used in natural product discovery laboratories. The genomics of secondary metabolite biosynthesis has recently evolved to the point where analysis of the genome of an organism can define its secondary metabolic capabilities. A genome scanning technique has been developed in our laboratories to greatly reduce the amount of sequencing required to define this capability [2,3]. This approach not only ascertains the potential of a producing organism, but it provides the scientist with a handle to identify, isolate and structurally define a specific metabolite. We have demonstrated this approach in the isolation and structural determination of an antifungal agent, ECO-02301 from Streptomyces aizunensis [4].In our continuing effort to find novel secondary metabolites from actinomycetes, we observed that two different streptomycetes, Streptomyces aculeolatus NRRL 18422 (a producer of the semi-naphthaquinone antibiotic, [5] and Streptomyces sp. Eco86 (a proprietary Ecopia strain) had similar gene clusters for type I polyketides with relatively few post-polyketide elaborative enzymes, but including an uncommon Baeyer-Villiger type monooxygenase. Analyses of these gene clusters led us to conclude that these microorganisms produce members of a group of very closely related secondary metabolites. Here, we report the isolation and identification of...

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“…(B. Shen, personal communication) recently found that the biosynthetic gene clusters for neocarzinostatin in S. carzinostaticus, 70 leinamycin in S. globispora 71 and C-1027 in S. atroolivaceus, 72 are all located on a giant linear plasmid ( Table 1). The same situation may be present in other cases, where the antibiotic clusters have not been located in spite of extensive biosynthetic studies.…”

Section: Other Giant Linear Plasmidsmentioning

confidence: 99%

Giant linear plasmids in Streptomyces: a treasure trove of antibiotic biosynthetic clusters

Kinashi

2010

J Antibiot

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Many giant linear plasmids have been isolated from Streptomyces by using pulsed-field gel electrophoresis and some of them were found to carry an antibiotic biosynthetic cluster(s); SCP1 carries biosynthetic genes for methylenomycin, pSLA2-L for lankacidin and lankamycin, and pKSL for lasalocid and echinomycin. Accumulated data suggest that giant linear plasmids have played critical roles in genome evolution and horizontal transfer of secondary metabolism. In this review, I summarize typical examples of giant linear plasmids whose involvement in antibiotic production has been studied in some detail, emphasizing their finding processes and interaction with the host chromosomes. A hypothesis on horizontal transfer of secondary metabolism involving giant linear plasmids is proposed at the end.

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Biosynthesis of the Enediyne Antitumor Antibiotic C-1027

Cited by 275 publications

References 24 publications

Benzoxacystol, a benzoxazine-type enzyme inhibitor from the deep-sea strain Streptomyces sp. NTK 935

Benzoxacystol, a benzoxazine-type enzyme inhibitor from the deep-sea strain Streptomyces sp. NTK 935

Isolation and Identification of Three New 5-Alkenyl-3,3(2H)-furanones from Two Streptomyces species using a Genomic Screening Approach

Giant linear plasmids in Streptomyces: a treasure trove of antibiotic biosynthetic clusters

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