Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus

Otten, Sharee L.; Ferguson, Jane; Hutchinson, C. Richard

doi:10.1128/jb.177.5.1216-1224.1995

Cited by 73 publications

(104 citation statements)

References 40 publications

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“…Other entries in the protein identification databases were also found in routine searches using the Orf2'" sequence, including DnrS and DauH from daunorubicin (daunomycin)-producing S. peucetius (Otten et al, 1995) and Streptomyces sp. strain C5 (Dickens et al, 1996), respectively, but the closest match (50 % identity) was found with the product of eryCZIl (orf8) from the erythromycin producer, Saccharopolyspora erythraea (Haydock, 1992).…”

Section: Resultsmentioning

confidence: 99%

Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors

Fish¹,

Cundliffe

1997

Microbiology

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Three glycosyltransferases are involved in tylosin biosynthesis in Streptomyces fradiae. The first sugar to be added to the polyketide aglycone (tylactone) is mycaminose and the gene encoding mycaminosyltransferase is oH2* (tyhW2). However, targeted disruption of od2* did not lead to the accumulation of tylactone under conditions that normally favour tylosin production; instead, the synthesis of tylactone was virtually abolished. This may, in part, have resulted from a polar effect on the expression of genes downstream of oH2*, particularly od4* (ccr) which encodes crotonyl-CoA reductase, an enzyme that supplies 4-carbon extender units for polyketide metabolism. However, that cannot be the entire explanation, since tylosin production was restored a t about 10% of the wild-type level when oH2* was re-introduced into the disrupted strain. When glycosylated precursors of tylosin were fed to the disrupted strain, they were converted to tylosin, confirming that two of the three glycosyltransferase activities associated with tylosin biosynthesis were still intact. Interestingly, however, tylactone also accumulated under such conditions and, to a much lesser extent, when tylosin was added to similar fermentations. It is concluded that glycosylated macrolides exert a pronounced positive effect on polyketide metabolism in S. fradiae. ;ity OfKeywords : tylosin production, glycosyltransferase, polyketide metabolism, Streptomyces fradiae INTRODUCTIONThe macrolide antibiotic, tylosin (Fig. l ) , is produced by Streptomyces fradiae via a combination of polyketide and 6-deoxyhexose metabolism. Glycosylation of tylactone, the cyclized polyketide product, always begins with the addition of mycaminose followed, in a preferred but not obligatory order, by deoxyallose and then mycarose to generate demethyl-macrocin. Stepwise bis 0-methylation then converts the deoxyallose moiety to mycinose as macrocin is produced and converted to tylosin (Baltz et al., 1983). Characterization of the tylosin biosynthetic pathway (Fig. 2) was facilitated by the availability of non-producing mutants of S. fradiae, generated using NTG (Baltz & Seno, 1981). Collectively, these exhibited nine distinct phenotypes in cross-feeding Abbreviations: OMT, 0-mycaminosyl-tylonolide; DMT, demycinosyltyl osi n. experiments and allowed 13 genetic loci (tylA-M) to be mapped (Fig. 3) following complementation studies using cloned fragments of tyl DNA (Beckmann et al.,

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Section: Resultsmentioning

confidence: 99%

Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors

Fish¹,

Cundliffe

1997

Microbiology

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“…Thus, there is a feed-forward mechanism of regulation in which the production of a small, apparently subinhibitory concentration of the antibiotic results in activation of planosporicin biosynthesis throughout the substrate mycelium, much of which has not reached the stage of maturity at which normal, stationary phase biosynthesis of the antibiotic would occur and thus ensuring that sufficient quantities of the lantibiotic are made to provide P. alba with a competitive advantage. Feed-forward regulation of antibiotic biosynthesis by an immature form of the antibiotic was proposed (but not demonstrated) for microbisporicin biosynthesis (19), and biosynthetic pathway intermediates, as well as the final product, have been postulated to activate export and potentially immunity mechanisms in streptomycetes (39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

Sherwood

Bibb

2013

Proc. Natl. Acad. Sci. U.S.A.

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Planosporicin is a ribosomally synthesized, posttranslationally modified peptide lantibiotic produced by the actinomycete Planomonospora alba. It contains one methyl-lanthionine and four lanthionine bridges and inhibits cell wall biosynthesis in other Gram-positive bacteria probably by binding to lipid II, the immediate precursor for cell wall biosynthesis. Planosporicin production, which is encoded by a cluster of 15 genes, is confined to stationary phase in liquid culture and to the onset of morphological differentiation when P. alba is grown on agar. This growth phase-dependent gene expression is controlled transcriptionally by three pathway-specific regulatory proteins: an extracytoplasmic function σ factor (PspX), its cognate anti-σ factor (PspW), and a transcriptional activator (PspR) with a C-terminal helix-turn-helix DNA-binding domain. Using mutational analysis, S1 nuclease mapping, quantitative RT-PCR, and transcriptional fusions, we have determined the direct regulatory dependencies within the planosporicin gene cluster and present a model in which subinhibitory concentrations of the lantibiotic function in a feed-forward mechanism to elicit high levels of planosporicin production. We show that in addition to acting as an antibiotic, planosporicin can function as an extracellular signaling molecule to elicit precocious production of the lantibiotic, presumably ensuring synchronous and concerted lantibiotic biosynthesis in the wider population and, thus, the production of ecologically effective concentrations of the antibiotic.

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“…demonstrated that DNR and DXR biosynthesis are regulated by the pathway-specific transcriptional activators dnrN (Otten et al, 1995) and dnrI (Madduri & Hutchinson, 1995 ;Stutzman-Engwall et al, 1992) (Fig. 1a).…”

Section: Our Studies Of the Molecular Biology Of Daunorubicin (Dnr) Amentioning

confidence: 99%

“…DnrI is related to other Streptomyces regulatory proteins such as actII-Orf4 and redD, all of which belong to the superfamily of SARP proteins (Wietzorrek & Bibb, 1997), and activates the transcription of the structural and resistance genes of the DNR and DXR gene cluster (Madduri & Hutchinson, 1995 ;StutzmanEngwall et al, 1992). DNA-binding studies have shown that DnrI binds near the k35 region of promoters controlling early-and late-acting genes of the DNR biosynthetic pathway (Tang et al, 1996) Daunorubicin biosynthesis gene is in turn regulated by the pseudo response regulator protein DnrN, which activates the transcription of dnrI (Furuya & Hutchinson, 1996 ;Otten et al, 1995). DnrN has been shown to bind specifically to the dnrI promoter region, but not to the promoter regions of three biosynthetic genes nor to its own promoter (Furuya & Hutchinson, 1996).…”

Section: Our Studies Of the Molecular Biology Of Daunorubicin (Dnr) Amentioning

confidence: 99%

“…These include actII-Orf4 (Fernandez-Moreno et al, 1991) and redD (Narva & Feitelson, 1990), which act as transcriptional activators of the actinorhodin and undecylprodigiosin biosynthetic pathways, respectively, in S. coelicolor. (Otten et al, 1995), showing the location of the apparent transcription start sites and assigned k10/k35 promoter regions and a small portion of the two ORFs. Only the restriction sites mentioned in the text are indicated.…”

Section: Introductionmentioning

confidence: 99%

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The dnrO gene encodes a DNA-binding protein that regulates daunorubicin production in Streptomyces peucetius by controlling expression of the dnrN pseudo response regulator gene

2000

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The dnrO gene is located adjacent to and divergently transcribed from the response regulator gene, dnrN, that activates the transcription of the dnrI gene, which in turn activates transcription of the daunorubicin biosynthesis genes in Streptomyces peucetius. Gene disruption and replacement of dnrO produced the dnrO ::aphII mutant strain and resulted in the complete loss of daunorubicin biosynthesis. Suppression of the dnrO ::aphII mutation by the introduction of dnrN or dnrI on a plasmid suggested that DnrO is required for the transcription of dnrN, whose product is known to be required for dnrI expression. These conclusions were supported by the effects of the dnrO mutation on expression of dnrO, dnrN and dnrI, as viewed by melC fusions to each of these regulatory genes. DnrO was overexpressed in Escherichia coli and the cell-free extract was used to conduct mobility shift DNA-binding assays. The results showed that DnrO binds specifically to the overlapping dnrN/dnrO p1 promoter region. Thus, DnrO may regulate the expression of both the dnrN and dnrO genes.

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Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus

Cited by 73 publications

References 40 publications

Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors

Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors

The antibiotic planosporicin coordinates its own production in the actinomycete Planomonospora alba

The dnrO gene encodes a DNA-binding protein that regulates daunorubicin production in Streptomyces peucetius by controlling expression of the dnrN pseudo response regulator gene

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