Simultaneous operation of the mevalonate and non-mevalonate pathways in the biosynthesis of isopentenly diphosphate in Streptomyces aeriouvifer

Seto, Haruo; Watanabe, Hiroyuki; Furihata, Kazuo

doi:10.1016/0040-4039(96)01787-x

Cited by 131 publications

(98 citation statements)

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“…strain A40644 (BE-40644 producer) [64], Streptomyces sp. strain CL190 (naphterpin producer) [65], Streptomyces sp. strain KO-3988 (furaquinocin producer) [66], and Chainia rubra (napyradiomycin producer) [67] (Fig.…”

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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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Studies on Biosynthetic Genes and Enzymes of Isoprenoids Produced by Actinomycetes

Dairi

2005

J Antibiot

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“…Specific and/or non-specific incorporations of ≥ 1% were obtained within 72 h of feeding with [3-14 C]-R,S-mevalonolactone and [U-14 C]-glyceraldehyde-3-phosphate but, as would be expected, a considerably lower percentage incorporation (0.1 -0.3%) was attained with [U-14 C]-glucose. In order to determine the specificity of incorporation, and hence the possible biosynthetic origin of the isoprenoid moieties, experiments involving the incorporation of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]-glucose into 4-nerolidylcatechol (1) were carried out. Different patterns of 13 C-enrichment in 1 would be expected depending on the pathway followed.…”

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“…A origem biossintética das unidades isoprênicas do 4-nerolidilcatecol (1), principal metabólito secundário de Potomorphe umbellata, foi investigada através da incorporação de glicose marcada com [ C] em 1 foi determinado por experimentos de RMN 13 C quantitativos. O padrão de marcação revelou que o precursor foi especificamente incorporado, e que as unidades isoprênicas presentes no 4-nerolidilcatecol são derivadas tanto do ácido mevalônico, quanto da via triose/piruvato.…”

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Biosynthetic origins of the isoprene units of 4-nerolidylcatechol in Potomorphe umbellata

Bergamo¹,

Kato

Bolzani³

et al. 2005

J. Braz. Chem. Soc.

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A origem biossintética das unidades isoprênicas do 4-nerolidilcatecol (1) 13 C]-glucose into 1 was determined by quantitative 13 C NMR spectroscopy. The labelling pattern revealed that the additive was specifically incorporated, and that the isoprene units of the sesquiterpenoid moiety of 4-nerolidylcatechol were derived from both the mevalonic acid and the triose/pyruvate pathways. The results indicate that both plastidic and cytoplasmic pathways are able to provide isopentenyl diphosphate units for the biosynthesis of 1.

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“…Some of the members of this genus, however, use the mevalonate pathway as well for production of terpenoids as secondary metabolites. Such examples include naphterpin [2], terpentecin [3], napyradiomycin [4], BE-40644 [5] and furaquinocin [6]. We were interested in this phenomenon and initiated a screen for terpenoids of actinomycete origin.…”

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Studies on Terpenoids Produced by Actinomycetes

et al. 2005

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As a result of screening for terpenoids produced by Actinomycetes, naphterpins B and C, two new congeners of naphterpin were isolated from Streptomyces sp. CL190 and their structures were determined by NMR spectral analysis. We were interested in this phenomenon and initiated a screen for terpenoids of actinomycete origin. As a first step we examined in detail the minor metabolites of a naphterpin producer, Streptomyces sp. CL190 [7], with the aim of isolating new terpenoids from this organism.Since most terpenoids are hydrophobic in nature, we examined lipophilic fraction of the fermentation broth of Streptomyces sp. CL190 by TLC, and fractions positive to vanillin-H 2 SO 4 color reaction were analyzed by 1 H-NMR.Fractions showing sharp methyl singlet signals were judged to contain terpenoids and subjected to further purification. As a result, we succeeded in isolating two terpenoids, naphterpins B and C from Streptomyces sp. CL-190. We report herein their structures and biological activities.Streptomyces sp. CL-190 was cultivated in 15 ml test tubes each containing 5 ml of PC-1 medium (starch 1%, polypepton 1%, meat extract 1% and molasses 1%, pH 7.2 before sterilization) 28°C for two days. Each one ml of the broth was transferred to 500 ml baffled Erlenmeyer flasks containing 100 ml of K-medium (starch 2.5%, soybean meal 1.5%, dry yeast 0.2% and CaCO 3 0.4%, pH 6.2 before sterilization) and cultivated on a rotary shaker at 28°C for 6 days. The fermentation broth was filtered and the filtrate was extracted with AcOEt. The mycelium was extracted with acetone and after removal of the acetone, the aqueous residue was extracted with AcOEt. Both solvent extracts were combined and concentrated in vacuo to give an oily residue which was subjected to flash column chromatography (silica gel column, 25ϫ480 mm, equilibrated with hexane : AcOEtϭ4 : 1). After washing the column with the same solvent, the column was eluted with 200 ml of CHCl 3 : MeOHϭ20 : 1. This fraction was concentrated under reduced pressure and the residue was purified by preparative TLC (Merck silica gel 60 F 254 , 20ϫ 20 cm) developed with a solvent (CHCl 3 : MeOHϭ20 : 1). Two yellow bands (Rfϭ0.31 and 0.28) were separately scraped off and eluted with AcOEt to give crude samples that were named naphterpin B and naphterpin C. Each

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Simultaneous operation of the mevalonate and non-mevalonate pathways in the biosynthesis of isopentenly diphosphate in Streptomyces aeriouvifer

Cited by 131 publications

References 12 publications

Studies on Biosynthetic Genes and Enzymes of Isoprenoids Produced by Actinomycetes

Studies on Biosynthetic Genes and Enzymes of Isoprenoids Produced by Actinomycetes

Biosynthetic origins of the isoprene units of 4-nerolidylcatechol in Potomorphe umbellata

Studies on Terpenoids Produced by Actinomycetes

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