Structure-activity relationships of virginiae butanolide C, an inducer of virginiamycin production in Streptomyces virginiae.

Nihira, Takuya; Shimizu, Yoshihiro; Kim, Hyun Soo; Yamada, Yasuhiro

doi:10.7164/antibiotics.41.1828

Cited by 65 publications

(45 citation statements)

References 10 publications

(2 reference statements)

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“…1A]), possess type-specific receptor proteins that recognize the tiny structural differences among the three types of autoregulators. The effectiveness of the autoregulators at extremely low concentrations, usually at a concentration of a few nanomolars (23), as well as the presence of receptor proteins of high ligand specificity (24,35,37), implies that the ␥-butyrolactone autoregulators should be regarded as Streptomyces hormones.…”

Section: Members Of the Filamentous Gram-positive Bacterial Genusmentioning

confidence: 99%

barS1, a Gene for Biosynthesis of a γ-Butyrolactone Autoregulator, a Microbial Signaling Molecule Eliciting Antibiotic Production inStreptomycesSpecies

2002

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From Streptomyces virginiae, in which production of streptogramin antibiotic virginiamycin M 1 and S is tightly regulated by a low-molecular-weight Streptomyces hormone called virginiae butanolide (VB), which is a member of the ␥-butyrolactone autoregulators, the hormone biosynthetic gene (barS1) was cloned and characterized by heterologous expression in Escherichia coli and by gene disruption in S. virginiae. The barS1 gene (a 774-bp open reading frame encoding a 257-amino-acid protein [M r , 27,095]) is situated in the 10-kb regulator island surrounding the VB-specific receptor gene, barA. The deduced BarS1 protein is weakly homologous to ␤-ketoacyl-acyl carrier protein/coenzyme A reductase and belongs to the superfamily of short-chain alcohol dehydrogenase. The function of the BarS1 protein in VB biosynthesis was confirmed by BarS1-dependent in vitro conversion of 6-dehydro-VB-A to VB-A, the last catalytic step in VB biosynthesis. Of the four possible enantiomeric products from racemic 6-dehydro-VB-A as a substrate, only the natural enantiomer of (2R,3R,6S)-VB-A was produced by the purified recombinant BarS1 (rBarS1), indicating that rBarS1 is the stereospecific reductase recognizing (3R)-isomer as a substrate and reducing it stereospecifically to the (6S) product. In the ⌬barS1 mutant created by homologous recombination, the production of VB as well as the production of virginiamycin was lost. The production of virginiamycin by the ⌬barS1 mutant was fully recovered by the external addition of VB to the culture, which indicates that the barS1 gene is essential in the biosynthesis of the autoregulator VBs in S. virginiae and that the failure of virginiamycin production was a result of the loss of VB production.

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Section: Members Of the Filamentous Gram-positive Bacterial Genusmentioning

confidence: 99%

barS1, a Gene for Biosynthesis of a γ-Butyrolactone Autoregulator, a Microbial Signaling Molecule Eliciting Antibiotic Production inStreptomycesSpecies

2002

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“…AS-1 medium, minimal medium with mannitol (Kieser et al, 2000) and ISP medium 2 were used for observing the morphological development of gene disruptants. For virginiamycin production, liquid f-medium was used as described previously (Nihira et al, 1988). For routine cloning and conjugation, Escherichia coli strains were grown on LB medium with the appropriate antibiotics, when necessary.…”

Section: Methodsmentioning

confidence: 99%

Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR

et al. 2009

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Two regulatory genes encoding a Streptomyces antibiotic regulatory protein (vmsS) and a response regulator (vmsT) of a bacterial two-component signal transduction system are present in the left-hand region of the biosynthetic gene cluster of the antibiotic virginiamycin, which is composed of virginiamycin M (VM) and virginiamycin S (VS), in Streptomyces virginiae. Disruption of vmsS abolished both VM and VS biosynthesis, with drastic alteration of the transcriptional profile for virginiamycin biosynthetic genes, whereas disruption of vmsT resulted in only a loss of VM biosynthesis, suggesting that vmsS is a pathway-specific regulator for both VM and VS biosynthesis, and that vmsT is a pathway-specific regulator for VM biosynthesis alone. Gene expression profiles determined by semiquantitative RT-PCR on the virginiamycin biosynthetic gene cluster demonstrated that vmsS controls the biosynthetic genes for VM and VS, and vmsT controls unidentified gene(s) of VM biosynthesis located outside the biosynthetic gene cluster. In addition, transcriptional analysis of a deletion mutant of vmsR located in the clustered regulatory region in the virginiamycin cluster (and which also acts as a SARP-family activator for both VM and VS biosynthesis) indicated that the expression of vmsS and vmsT is under the control of vmsR, and vmsR also contributes to the expression of VM and VS biosynthetic genes, independent of vmsS and vmsT. Therefore, coordinated virginiamycin biosynthesis is controlled by three pathway-specific regulators which hierarchically control the expression of the biosynthetic gene cluster.

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“…mosil 5C 18 (4.6 by 100 mm; Nacalai Tesque, Kyoto, Japan); flow rate, 0.75 ml/min; temperature, 40°C; detection, UV radiation at 305 nm; elution, 5 min with 20% CH 3 CN containing 0.1% trifluoroacetic acid followed by the linear increase of CH 3 CN from 20 to 80% for 15 min. The amounts of VB were determined by measuring the VB-dependent production of VM (20). VB binding activity was assayed by the ammonium sulfate precipitation method (10) with 3 H-labeled VB-C 7 (54.6 Ci/mmol) in the presence and absence of 2,000-fold cold VB-C.…”

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confidence: 99%

Identification by Gene Deletion Analysis of a Regulator, VmsR, That Controls Virginiamycin Biosynthesis in Streptomyces virginiae

et al. 2000

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Virginiae butanolide (VB)-BarA of Streptomyces virginiae is one of the newly discovered pairs of a butyrolactone autoregulator and a corresponding receptor protein of Streptomyces species and regulates the production of the antibiotic virginiamycin (VM) in S. virginiae. The gene vmsR was found to be situated 4.7 kbp upstream of the barA gene, which encodes the VB-specific receptor. The vmsR product was predicted to be a regulator of VM biosynthesis based on its high homology to some Streptomyces pathway-specific transcriptional regulators for the biosynthetic gene clusters of polyketide antibiotics, such as Streptomyces peucetius DnrI (47.5% identity, 84.3% similarity), which controls daunorubicin biosynthesis. A vmsR deletion mutant was created by homologous recombination. Neither virginiamycin M 1 nor virginiamycin S was produced in the vmsR mutant, while amounts of VB and BarA similar to those produced in the wild-type strain were detected. Reverse transcription-PCR analyses confirmed that the vmsR deletion had no deleterious effects on the transcription of the vmsR-surrounding genes, indicating that VmsR is a positive regulator of VM biosynthesis in S. virginiae.Streptomycetes are gram-positive filamentous bacteria that are well-known for producing a vast array of bioactive compounds, including more than 70% of commercially important antibiotics. The production of antibiotics by these organisms is regulated by a variety of physiological and nutritional conditions and is coordinated with processes of morphological differentiation, such as the formation of aerial mycelia and spores. Despite many years of research on antibiotics driven by their commercial importance, the overall regulatory pathway governing antibiotic production is still poorly understood. A detailed knowledge of the signal cascade and the genetic components involved in antibiotic production should permit construction of strains that can overproduce these commercially important compounds.Antibiotic production and/or morphological differentiation is controlled in several Streptomyces species by low-molecularweight compounds called butyrolactone autoregulators (32). To date, 11 butyrolactone autoregulators have been chemically identified and classified into three types based on minor structural differences in their C-2 side chains: (i) the virginiae butanolide (VB) type, containing a 6-␣-hydroxy group (13, 31); (ii) the IM-2 type, containing a 6-␤-hydroxy group (25, 27); and (iii) the A-factor type, containing a 6-keto group (16). Their effectiveness at nanomolar concentrations, as well as the presence in these species of specific receptor proteins (BarA as a VB-specific receptor in Streptomyces virginiae [9,10,21], FarA as an IM-2-specific receptor in Streptomyces lavendulae 28], and ArpA as an A-factor-specific receptor in Streptomyces griseus [22]) as mediators of autoregulator signaling, implies that they should be regarded as Streptomyces hormones.VB-BarA of S. virginiae has been among the most frequently studied pairs and is known to regula...

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Structure-activity relationships of virginiae butanolide C, an inducer of virginiamycin production in Streptomyces virginiae.

Cited by 65 publications

References 10 publications

barS1, a Gene for Biosynthesis of a γ-Butyrolactone Autoregulator, a Microbial Signaling Molecule Eliciting Antibiotic Production inStreptomycesSpecies

barS1, a Gene for Biosynthesis of a γ-Butyrolactone Autoregulator, a Microbial Signaling Molecule Eliciting Antibiotic Production inStreptomycesSpecies

Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR

Identification by Gene Deletion Analysis of a Regulator, VmsR, That Controls Virginiamycin Biosynthesis in Streptomyces virginiae

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