The pathway-specific regulator AveR from Streptomyces avermitilis positively regulates avermectin production while it negatively affects oligomycin biosynthesis

Guo, Jia; Zhao, Jinlei; Li, Lili; Chen, Zhi; Wen, Ying; Li, Jilun

doi:10.1007/s00438-009-0502-2

Cited by 73 publications

(79 citation statements)

References 21 publications

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“…ChIP-on-chip experiments and promoter activity assays showed that the ave genes, for avermectin, and the olm genes, for oligomycin biosynthesis, were targets of AveR, leading to positive and negative regulation of these clusters, respectively. 47 THE phoRP-phoU GENE CLUSTER IN S. avermitilis The arrangement of the phoRP-phoU gene cluster in S. avermitilis is identical to that of S. coelicolor. Both phoRP genes are transcribed divergently from phoU.…”

Section: Avermectin and The Avermectin Gene Cluster In Streptomyces Amentioning

confidence: 99%

The master regulator PhoP coordinates phosphate and nitrogen metabolism, respiration, cell differentiation and antibiotic biosynthesis: comparison in Streptomyces coelicolor and Streptomyces avermitilis

2017

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Phosphate limitation is important for production of antibiotics and other secondary metabolites in Streptomyces. Phosphate control is mediated by the two-component system PhoR-PhoP. Following phosphate depletion, PhoP stimulates expression of genes involved in scavenging, transport and mobilization of phosphate, and represses the utilization of nitrogen sources. PhoP reduces expression of genes for aerobic respiration and activates nitrate respiration genes. PhoP activates genes for teichuronic acid formation and reduces expression of genes for phosphate-rich teichoic acid biosynthesis. In Streptomyces coelicolor, PhoP repressed several differentiation and pleiotropic regulatory genes, which affects development and indirectly antibiotic biosynthesis. A new bioinformatics analysis of the putative PhoP-binding sequences in Streptomyces avermitilis was made. Many sequences in S. avermitilis genome showed high weight values and were classified according to the available genetic information. These genes encode phosphate scavenging proteins, phosphate transporters and nitrogen metabolism genes. Among of the genes highlighted in the new studies was aveR, located in the avermectin gene cluster, encoding a LAL-type regulator, and afsS, which is regulated by PhoP and AfsR. The sequence logo for S. avermitilis PHO boxes is similar to that of S. coelicolor, with differences in the weight value for specific nucleotides in the sequence. INTRODUCTIONPhosphate is one of the essential nutrients of all living beings. In early studies, Martín and Demain 1 reported that, following phosphate starvation, there is a change in the metabolism of the antibiotic producing strains, which causes the slowdown of primary metabolism and triggers production of secondary metabolites. This early hypothesis has been largely confirmed by the research developed in the last few decades and is discussed in more detail below taking into account recent developments in the coordination of secondary metabolism. The aim of this article is to present an up-to-date integrative view of the PhoP regulation of metabolism in Streptomyces.

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Section: Avermectin and The Avermectin Gene Cluster In Streptomyces Amentioning

confidence: 99%

The master regulator PhoP coordinates phosphate and nitrogen metabolism, respiration, cell differentiation and antibiotic biosynthesis: comparison in Streptomyces coelicolor and Streptomyces avermitilis

2017

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“…The aveR gene encodes a pathway-specific activator essential for transcription of all avermectin biosynthetic genes (6,7). To test whether SAV7471 regulated avermectin production through a pathway-specific activator, we performed RT-PCR analysis in order to determine the expression levels of aveR and of the biosynthetic gene aveA1 in the SAV7471 deletion strain D7471, SAV7471-overexpression strain O7471, and in the wild-type strain ATCC 31267.…”

Section: Resultsmentioning

confidence: 99%

“…The polyketide chain is subsequently cyclized, glycosylated at C-13 with the attachment of two oleandrose sugars, and methylated at the hydroxyl group of C-5 (5). The aveR gene in the avermectin biosynthetic gene cluster encodes a pathway-specific activator essential for transcription of all avermectin biosynthetic genes (6,7).…”

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Characterization of SAV7471, a TetR-Family Transcriptional Regulator Involved in the Regulation of Coenzyme A Metabolism in Streptomyces avermitilis

et al. 2013

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The role of a tetR transcriptional regulatory gene (SAV7471) in avermectin production in the Gram-positive soil bacterium Streptomyces avermitilis was investigated by gene deletion, complementation, and overexpression experiments. Gene deletion of the SAV7471 open reading frame resulted in avermectin overproduction. The deletion also resulted in overexpression of SAV7472-SAV7473 transcripts, which encode a protein of unknown function and a flavoprotein possibly involved in pantothenate and coenzyme A (CoA) metabolism. EMSAs and footprinting assays showed that SAV7471 can bind to two palindromic sequences with high similarity in the intergenic region between SAV7471 and SAV7472, a region that contains the apparent transcription start sites for each gene detected by rapid amplification of 5= cDNA ends (5=-RACE). In addition to SAV7472-SAV7473, at least two genes (SAV1104 and SAV1258) involved in CoA metabolism are negatively controlled by SAV7471. By negatively regulating the transcription of the target genes SAV7472-SAV7473 and other genes involved in CoA metabolism, SAV7471 may affect cellular metabolic flux and may thereby indirectly regulate avermectin biosynthesis.

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“…The 82-kb ave gene cluster that controls avermectin biosynthesis includes 18 open reading frames (ORFs) (9). The gene aveR, located at the left end of the gene cluster, encodes a cluster-situated LuxR family activator essential for transcription of all ave structural genes (10,11). The factors that trigger the transcription of aveR and the detailed regulatory mechanisms of avermectin biosynthesis remain unclear.…”

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Increasing Avermectin Production in Streptomyces avermitilis by Manipulating the Expression of a Novel TetR-Family Regulator and Its Target Gene Product

Liu

Zhang

Guo

et al. 2015

Appl Environ Microbiol

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Avermectins produced by Streptomyces avermitilis are commercially important anthelmintic agents. The detailed regulatory mechanisms of avermectin biosynthesis remain unclear. Here, we identified SAV3619, a TetR-family transcriptional regulator designated AveT, to be an activator for both avermectin production and morphological differentiation in S. avermitilis. AveT was shown to indirectly stimulate avermectin production by affecting transcription of the cluster-situated activator gene aveR. AveT directly repressed transcription of its own gene (aveT), adjacent gene pepD2 (sav_3620), sav_7490 (designated aveM), and sav_7491 by binding to an 18-bp perfect palindromic sequence (CGAAACGKTKYCGTTTCG, where K is T or G and Y is T or C and where the underlining indicates inverted repeats) within their promoter regions. aveM (which encodes a putative transmembrane efflux protein belonging to the major facilitator superfamily [MFS]), the important target gene of AveT, had a striking negative effect on avermectin production and morphological differentiation. Overexpression of aveT and deletion of aveM in wild-type and industrial strains of S. avermitilis led to clear increases in the levels of avermectin production. In vitro gel-shift assays suggested that C-5-O-B1, the late pathway precursor of avermectin B1, acts as an AveT ligand. Taken together, our findings indicate positive-feedback regulation of aveT expression and avermectin production by a late pathway intermediate and provide the basis for an efficient strategy to increase avermectin production in S. avermitilis by manipulation of AveT and its target gene product, AveM. Soil-dwelling species of Streptomyces produce about half of currently known antibiotics (including antibacterial, anticancer, anthelmintic, and immunosuppressive agents) during their complex morphological differentiation cycle (1) and have many important medical and commercial applications. Antibiotic biosynthesis is controlled by large gene clusters, usually including cluster-situated regulators (CSRs). These CSRs are at the lowest level of the complex regulatory network for antibiotic biosynthesis and are controlled by various higher-level pleiotropic regulators in response to developmental state, population density, environmental signals, and physiological signals (2-4).The species Streptomyces avermitilis produces avermectins, a series of 16-membered macrocyclic lactones (termed A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b) that are excellent anthelmintic agents with high potency, broad-spectrum activity against various arthropod and nematode parasites, and a low level of side effects on the host (5, 6). Of the eight avermectin components, B1a has the highest insecticidal activity (7). Avermectins are a commercially important group of antibiotics with annual worldwide sales of ϳ$850 million (8) and are widely applied in the agricultural, veterinary, and medical fields. The 82-kb ave gene cluster that controls avermectin biosynthesis includes 18 open reading frames (ORFs) (9). The gene aveR, loc...

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The pathway-specific regulator AveR from Streptomyces avermitilis positively regulates avermectin production while it negatively affects oligomycin biosynthesis

Cited by 73 publications

References 21 publications

The master regulator PhoP coordinates phosphate and nitrogen metabolism, respiration, cell differentiation and antibiotic biosynthesis: comparison in Streptomyces coelicolor and Streptomyces avermitilis

The master regulator PhoP coordinates phosphate and nitrogen metabolism, respiration, cell differentiation and antibiotic biosynthesis: comparison in Streptomyces coelicolor and Streptomyces avermitilis

Characterization of SAV7471, a TetR-Family Transcriptional Regulator Involved in the Regulation of Coenzyme A Metabolism in Streptomyces avermitilis

Increasing Avermectin Production in Streptomyces avermitilis by Manipulating the Expression of a Novel TetR-Family Regulator and Its Target Gene Product

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