Isolation and characterization of terpentecin, a new antitumor antibiotic.

Tamamura, Tsuyoshi; Sawa, Tsutomu; Isshiki, Kunio; Masuda, Tohru; Homma, Yoshiko; Iinuma, Hisae; Naganawa, Hiroshi; Hamada, Masa; Takeuchi, Tomio; Umezawa, Hamao

doi:10.7164/antibiotics.38.1664

Cited by 58 publications

(37 citation statements)

References 11 publications

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“…The producing strain, compound name, activities of the compounds, reported by year, are shown in Table 3. 1,10,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] Setamycin possesses antitrichomonal and antifungal activities. Phosalacine possesses herbicidal activity.…”

Section: Diversity Of Biological Active Compounds Produced By Kitasatmentioning

confidence: 99%

Genus Kitasatospora, taxonomic features and diversity of secondary metabolites

Takahashi

2017

J Antibiot

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The genus Kitasatospora was proposed in 1982. Although Kitasatospora strains resemble Streptomyces strains in morphology, they are clearly different in cell-wall composition, as they contain both LL-and meso-diaminopimelic acid. Aerial and submerged spores contain LL − , while vegetative and submerged mycelia contain mainly meso-in their cell walls. Currently, 23 species have been validly proposed. Members of the genus Kitasatospora form a tight cluster and represent a legitimate genus distinct from Streptomyces on the basis of phylogenetic analysis of 16S rRNA gene sequences. A variety of biologically active compounds have been found from Kitasatospora strains and structures of these compounds are extremely diverse. Genome sequences of 15 strains published so far are about 7-9 Mb in size and contain many genes governing secondary metabolites.

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Section: Diversity Of Biological Active Compounds Produced By Kitasatmentioning

confidence: 99%

Genus Kitasatospora, taxonomic features and diversity of secondary metabolites

Takahashi

2017

J Antibiot

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“…4A) producer, was selected as the target because we also wanted to clone a diterpene cyclase gene responsible for the biosynthesis of TP in addition to the MV pathway genes was essential. Since TP possesses antibacterial activity [12] and has been shown to be mainly synthesized via the MV pathway [63], we expected that the MV pathway defective mutants would be present in TP non-producers, which could be easily detected by a bioassay. By treating the spores of the TP producer with a …”

Section: Cloning and Analysis Of A Mevalonate Pathway Gene Cluster Frmentioning

confidence: 99%

Studies on Biosynthetic Genes and Enzymes of Isoprenoids Produced by Actinomycetes

Dairi

2005

J Antibiot

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Most Streptomyces strains are equipped with only the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for the formation of isopentenyl diphosphate, a common precursor of isoprenoids. In addition to this pathway, some Streptomyces strains possess the mevalonate (MV) pathway via which isoprenoid antibiotics are produced. We have recently cloned and analyzed the MV pathway gene clusters and their flanking regions from terpentecin, BE-40644, and furaquinocin A producers. All these clusters contained genes coding for mevalonate kinase, mevalonate diphosphate decarboxylase, phosphomevalonate kinase, type 2 IPP isomerase, HMGCoA reductase, and HMG-CoA synthase. The order of each of the open reading frames (ORFs) is also the same, and the respective homologous ORFs show more than 70% amino acid identity with each other. In contrast to these conservative gene organizations, the biosynthetic genes of terpentecin, BE-40644, and furaquinocin A were located just upstream and/or downstream of the MV pathway gene cluster. These facts suggested that all the actinomycete strains possessing both the MV and MEP pathways produce isoprenoid compounds and the biosynthetic genes of one of these isoprenoids usually exist adjacent to the MV pathway gene cluster. Therefore, when the presence of the MV cluster is detected by molecular genetic techniques, isoprenoids may be produced by the cultivation of these actinomycete strains. During the course of these studies, we identified diterpene cyclases possessing unique primary structures that differ from those of eukaryotes and catalyze unique reactions.Keywords isoprenoid, mevalonate pathway, biosynthesis, cyclase, Actinomycetes IntroductionActinomycete strains usually produce a number of secondary metabolites that often possess pharmaceutical activities. Therefore, for a long time, the strains have been used for many screenings to find novel, medically useful compounds. Consequently, more than 60 percent of the known antibiotics, including not only antibacterial antibiotics but also bioactive microbial compounds, have been reported to be produced by actinomycetes [1]. Presently, such pharmaceutically important, novel compounds can be found in the culture broth of actinomycete strains by screening rare actinomycetes, developing new screening strategies, employing sensitive assay methods for the detection of low concentrations of antibiotics, etc. However, sometimes, "semi-new antibiotics"-derivatives of known antibiotics-were isolated; discovering novel antibiotics every year became very difficult.In the past two decades, recombinant DNA technology has come into play in this field. Gene clusters encoding many natural products have been cloned and characterized. Moreover, whole-genome sequencing has uncovered hundreds of candidates for secondary metabolic pathways. Among them, the biosynthetic machinery of nonribosomal peptide and polyketide natural products has been extensively investigated [2ϳ7]. Recent progress in the application of combinatorial biosynthesis methods to these bi...

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“…S. griseolosporeus strain MF730-N6 (a TP producer), which was formerly classified in the genus Kitasatosporia (41), was used for the cloning experiment. The media and growth conditions used for strain MF730-N6 were those described by Tamamura et al (41). S. lividans TK23 (17) and pWHM860 (a gift from C. R. Hutchinson, Kosan Biosciences Inc., Hayward, Calif.), a derivative of plasmid pWHM3 (44), were used for heterologous expression of the TP biosynthetic genes.…”

Section: Chemicals [␣-mentioning

confidence: 99%

Eubacterial Diterpene Cyclase Genes Essential for Production of the Isoprenoid Antibiotic Terpentecin

Dairi

Hamano

Kuzuyama³

et al. 2001

J Bacteriol

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). Sequence analysis in the upstream region of the cluster revealed seven new ORFs, ORF8 to ORF14, which were suggested to encode TP biosynthetic genes. We constructed two mutants, in which ORF11 and ORF12, which encode a protein showing similarities to eukaryotic diterpene cyclases (DCs) and a eubacterial pentalenene synthase, respectively, were inactivated by gene disruptions. The mutants produced no TP, confirming that these cyclase genes are essential for the production of TP. The two cyclase genes were also expressed in Streptomyces lividans together with the GGDP synthase gene under the control of the ermE* constitutive promoter. The transformant produced a novel cyclic diterpenoid, ent-clerod-3,13(16),14-triene (terpentetriene), which has the same basic skeleton as TP. The two enzymes, each of which was overproduced in Escherichia coli and purified to homogeneity, converted GGDP into terpentetriene. To the best of our knowledge, this is the first report of a eubacterial DC.Isoprenoids are the largest single family of compounds found in nature, with over 22,000 known examples (12), and can be classified into several groups based on the number of C 5 units derived from isopentenyl diphosphate (IPP), such as monoterpenes (C 10 ), sesquiterpenes (C 15 ), diterpenes (C 20 ), and triterpenes (C 30 ), etc. (12). These compounds are biosynthesized from the corresponding prenyl diphosphate. Geranyl diphosphate gives rise to monoterpenes, farnesyl diphosphate gives rise to sesquiterpenes, and geranylgeranyl diphosphate (GGDP) gives rise to diterpenes (9, 29) (Fig. 1). In many cases, these prenyl diphosphates undergo a range of cyclizations to produce the parent skeletons of each class, followed by a variety of modifications to give many thousands of different isoprenoid metabolites (9, 29).A variety of isoprenoid synthases (cyclases), most of which are from plants and fungi, have been purified and extensively studied (12). As for the genes encoding isoprenoid cyclases, more than 30 eukaryotic isoprenoid synthases have been cloned as cDNAs (9, 29). On the other hand, there have been few reports about eubacterial isoprenoid cyclases and genes because the vast majority of isoprenoids are produced by eukaryotes. Pentalenene synthase, a sesquiterpene cyclase from a Streptomyces strain (10), and squalene-hopene cyclases, triterpene cyclases from bacteria, are the only examples (22,32,34,35,42,46). There are no reports, to the best of our knowledge, about eubacterial monoterpene cyclases and diterpene cyclases (DCs).We have been studying the biosynthesis of isoprenoid antibiotics produced by actinomycetes. Although actinomycetes produce approximately 70% of all natural compounds, a very limited number of isoprenoid compounds are known to be produced by them (30). The gene cluster containing the mevalonate pathway genes used to synthesize IPP had previously been cloned from Streptomyces griseolosporeus strain MF730-N6, a diterpene antibiotic terpentecin (TP) producer (15). The GGDP synthase gene encoding the enzyme catalyz...

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Isolation and characterization of terpentecin, a new antitumor antibiotic.

Cited by 58 publications

References 11 publications

Genus Kitasatospora, taxonomic features and diversity of secondary metabolites

Genus Kitasatospora, taxonomic features and diversity of secondary metabolites

Studies on Biosynthetic Genes and Enzymes of Isoprenoids Produced by Actinomycetes

Eubacterial Diterpene Cyclase Genes Essential for Production of the Isoprenoid Antibiotic Terpentecin

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