Positive control of tylosin biosynthesis: pivotal role of TylR

Stratigopoulos, George; Bate, Neil; Cundliffe, Eric

doi:10.1111/j.1365-2958.2004.04347.x

Cited by 47 publications

(55 citation statements)

References 44 publications

(73 reference statements)

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“…In S. fradiae, the receptor protein TylP repressed the expression of the SARP gene tylS , which in turn resulted in the repression of tylR, encoding a pathway-specific activator in tylosin biosynthesis (Stratigopoulos et al, 2004). In S. pristinaespiralis, the receptor SpbR was bound to the promoter of the SARP gene papR1 and regulated pristinamycin synthesis (Folcher et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

γ-Butyrolactone autoregulator-receptor system involved in lankacidin and lankamycin production and morphological differentiation in Streptomyces rochei

et al. 2007

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An afsA homologue (srrX) and three c-butyrolactone receptor gene homologues (srrA, srrB and srrC) are coded on the giant linear plasmid pSLA2-L in Streptomyces rochei 7434AN4, a producer of two polyketide antibiotics, lankacidin and lankamycin. Construction of gene disruptants and their phenotypic study revealed that srrX and srrA make a c-butyrolactone receptor system in this strain. Addition of a c-butyrolactone fraction to an srrX-deficient mutant restored the production of lankacidin and lankamycin, indicating that the SrrX protein is not necessary for this event. In addition to a positive effect on antibiotic production, srrX showed a negative effect on morphological differentiation. The receptor gene srrA reversed both effects of srrX, while the second receptor gene homologue srrC had only a positive function in spore formation. Furthermore, disruption of the third homologue srrB greatly increased the production of lankacidin and lankamycin. Electron microscopic analysis showed that aerial mycelium formation stopped at a different stage in the srrA and srrC mutants. Overall, these results indicated that srrX, srrA, srrB and srrC constitute a complex regulatory system for antibiotic production and morphological differentiation in S. rochei. INTRODUCTIONThe filamentous Gram-positive soil bacteria of the genus Streptomyces are characterized by three distinct properties: linear chromosome, complex morphological differentiation and ability to produce varieties of secondary metabolites including antibiotics. Antibiotic biosynthetic genes in Streptomyces species usually form a condensed gene cluster on the chromosome. However, several giant linear plasmids encoding an antibiotic gene cluster(s) have been isolated: SCP1 in Streptomyces coelicolor A3(2) carries the biosynthetic gene cluster for methylenomycin (Bentley et al., 2004;Chater & Bruton, 1985;Kinashi et al., 1987;Redenbach et al., 1998), pPZG103 in Streptomyces rimosus has that for oxytetracycline (Gravius et al., 1994; Pandza et al., 1998) and pSLA2-L in Streptomyces rochei has those for lankacidin and lankamycin (Arakawa et al., 2005(Arakawa et al., , 2006Mochizuki et al., 2003;Suwa et al., 2000).S. rochei strain 7434AN4 contains three large linear plasmids (pSLA2-L, -M and -S) (Kinashi et al., 1994) and produces two structurally unrelated polyketide antibiotics, the 17-membered macrocyclic lankacidin and the 14-membered macrolide lankamycin (Fig. 1a). We have been studying the function of the largest linear plasmid pSLA2-L in antibiotic production, and finally determined its 210 614 bp nucleotide sequence (Mochizuki et al., 2003). It was revealed that pSLA2-L contains an unusually condensed gene organization for secondary metabolism (Fig. 1b); two type I PKS gene clusters for lankacidin (lkc, orf4-orf18) and lankamycin (lkm, orf24-orf53), a cryptic type II PKS gene cluster (roc, orf62-orf70) and a carotenoid biosynthetic gene cluster (crt, orf104-orf110). In addition, many regulatory genes were identified on pSLA2-L, including all the homologues in t...

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Section: Discussionmentioning

confidence: 99%

γ-Butyrolactone autoregulator-receptor system involved in lankacidin and lankamycin production and morphological differentiation in Streptomyces rochei

et al. 2007

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“…Enhanced expression of a pathway-specific transcriptional activator gene causes increased production of the respective secondary metabolite. Examples are dnrI for daunorubicin in S. peucetius (34), redD for undecylprodigiosin (37) and actIIorf4 for actinorhodin (8) in S. coelicolor A3(2), ccaR for cephamycin and clavulanic acid in S. clavuligerus (28), and tylR for tylosin in Streptomyces fradiae (33). Furthermore, introduction of actII-orf4 into S. lividans awakens the "sleeping" act genes, resulting in overproduction of actinorhodin (6).…”

Section: Discussionmentioning

confidence: 99%

A-Factor and Phosphate Depletion Signals Are Transmitted to the Grixazone Biosynthesis Genes via the Pathway-Specific Transcriptional Activator GriR

et al. 2007

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Grixazone (GX), which is a diffusible yellow pigment containing a phenoxazinone chromophore, is one of the secondary metabolites under the control of A-factor (2-isocapryloyl-3R-hydroxymethyl-␥-butyrolactone) in Streptomyces griseus. GX production is also induced by phosphate starvation. The whole biosynthesis gene cluster for GX was cloned and characterized. The gene cluster consisting of 13 genes contained six transcriptional units, griT, griSR, griR, griAB, griCDEFG, and griJIH. During cultivation in a phosphate-depleted medium, the six promoters were activated in the order (i) griR, (ii) griC and griJ, and (iii) griT, griS, and griA. Disruption of griR, which encodes a SARP family transcriptional regulator, abolished the transcriptional activation of all other genes in the cluster. In addition, ectopic expression of griR from a constitutively active promoter resulted in GX overproduction even in the absence of AdpA, a key transcriptional activator in the A-factor regulatory cascade, and in the presence of phosphate at a high concentration. GriR monomers bound direct repeat sequences in the griC and griJ promoters in a cooperative manner. Therefore, the early active genes (griCDEFG and griJIH), all of which, except for griG (which encodes a transporter-like protein), encode the GX biosynthesis enzymes, were directly activated by GriR. The transcription of griR was greatly reduced in the presence of phosphate at a high concentration and was hardly detected in the absence of AdpA. These findings showed that both A-factor and phosphate depletion signals were required for griR transcription and both signals were transmitted to the GX biosynthesis genes solely via the griR promoter.A-factor (2-isocapryloyl-3R-hydroxymethyl-␥-butyrolactone; see Fig. 7 for its structure) is a chemical signaling molecule, or a microbial hormone, that triggers secondary metabolism and cell differentiation in Streptomyces griseus (10,25). A-factor is gradually accumulated in a growthdependent manner by the activity of AfsA, which is the key enzyme for A-factor biosynthesis. We have recently established the whole A-factor biosynthesis pathway, including the function of AfsA, which catalyzes ␤-ketoacyl transfer between dihydroxyacetone phosphate and 8-methyl-3-oxononanoyl-acyl carrier protein (12). When the concentration of A-factor reaches a critical level at or near the middle of the exponential growth phase, it binds the A-factor receptor protein (ArpA), which has bound and repressed the promoter of adpA, and dissociates ArpA from the promoter, thus inducing transcription of adpA (26). AdpA then activates a number of genes required for secondary metabolism and morphological differentiation, forming an AdpA regulon (13, 27). Members of the AdpA regulon that are involved in secondary metabolism include strR, the pathway-specific transcriptional activator for streptomycin biosynthesis (38), and an open reading frame (ORF) that encodes a probable pathwayspecific regulator for a polyketide compound (39).Grixazone (GX) is a diffusible yello...

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“…Putative regulatory genes present in the cluster, such as rapR, rapS, rapY, and rapK, in addition to rapH and rapG, may have a direct or indirect influence on these aspects of biosynthesis. The complexity of regulatory systems would also suggest that one or more regulatory gene products may be dependent on and/or act in concert with another to affect a positive or negative regulatory role, e.g., as observed for tylosin (41) and nystatin (39) biosynthesis. The work presented here represents a first step in exploring the complexity of the regulation of rapamycin biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The study of polyketide synthase (PKS) systems has revealed a number of associated regulatory proteins (3), but much remains unknown about the regulation of the biosynthesis of some of the more complex polyketides (1,12,41), although the complexity of these regulatory networks is beginning to be appreciated. The expression of PKS gene cluster elements is often controlled by a number of different families of regulatory proteins that can have either a pathway-specific or a pleiotropic mode of action, affecting a broader range of morphological and physiological processes, including secondary metabolite production (3).…”

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Roles of rapH and rapG in Positive Regulation of Rapamycin Biosynthesis in Streptomyces hygroscopicus

Kuščer¹,

Coates²,

Challis³

et al. 2007

J Bacteriol

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Rapamycin is an important macrocyclic polyketide produced by Streptomyces hygroscopicus and showing immunosuppressive, antifungal, and antitumor activities as well as displaying anti-inflammatory and neuroregenerative properties. The immense pharmacological potential of rapamycin has led to the production of an array of analogues, including through genetic engineering of the rapamycin biosynthetic gene cluster. This cluster contains several putative regulatory genes. Based on DNA sequence analysis, the products of genes rapH and rapG showed high similarities with two different families of transcriptional activators, LAL and AraC, respectively. Overexpression of either gene resulted in a substantial increase in rapamycin biosynthesis, confirming their positive regulatory role, while deletion of both from the chromosome of S. hygroscopicus resulted in a complete loss of antibiotic production. Complementation studies indicated an essential role of the RapG regulator for rapamycin biosynthesis and a supportive role of RapH. A direct effect of rapH and rapG gene products on the promoter of the rapamycin polyketide synthase operon, rapA-rapB, was observed using the chalcone synthase gene rppA as a reporter system.

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Positive control of tylosin biosynthesis: pivotal role of TylR

Cited by 47 publications

References 44 publications

γ-Butyrolactone autoregulator-receptor system involved in lankacidin and lankamycin production and morphological differentiation in Streptomyces rochei

γ-Butyrolactone autoregulator-receptor system involved in lankacidin and lankamycin production and morphological differentiation in Streptomyces rochei

A-Factor and Phosphate Depletion Signals Are Transmitted to the Grixazone Biosynthesis Genes via the Pathway-Specific Transcriptional Activator GriR

Roles of rapH and rapG in Positive Regulation of Rapamycin Biosynthesis in Streptomyces hygroscopicus

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