Regulation of Lankamycin Biosynthesis inStreptomyces rocheiby Two SARP Genes,srrYandsrrZ

Suzuki, Toshihiro; Mochizuki, Susumu; Yamamoto, Shouji; Arakawa, Kenji; Kinashi, Haruyasu

doi:10.1271/bbb.90927

Cited by 43 publications

(48 citation statements)

References 31 publications

(42 reference statements)

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“…In EMSAs, PapR4 bound to the papR2 promoter region, which suggests that it may have an activating function in papR2 gene transcription. A comparable SARP-SARP system has been described for the lankamycin/ lankacidin producer S. rochei, whereby the SARP-type regulator SrrY activates the transcription of the SARP gene srrZ (45). In summary, we can state that each of the pristinamycin SARPs exerts its individual role during pristinamycin biosynthesis.…”

Section: Discussionmentioning

confidence: 75%

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Mast

Guezguez

Handel

et al. 2015

Appl Environ Microbiol

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Pristinamycin production in Streptomyces pristinaespiralis Pr11 is tightly regulated by an interplay between different repressors and activators. A ␥-butyrolactone receptor gene (spbR), two TetR repressor genes (papR3 and papR5), three SARP (Streptomyces antibiotic regulatory protein) genes (papR1, papR2, and papR4), and a response regulator gene (papR6) are carried on the large 210-kb pristinamycin biosynthetic gene region of Streptomyces pristinaespiralis Pr11. A detailed investigation of all pristinamycin regulators revealed insight into a complex signaling cascade, which is responsible for the fine-tuned regulation of pristinamycin production in S. pristinaespiralis. Streptomycetes are filamentous, Gram-positive soil bacteria that are well known for their ability to produce varieties of bioactive secondary metabolites, including more than 70% of the commercially important antibiotics (1). The production of antibiotics is controlled by a vast array of physiological and nutritional conditions, communicated by extracellular and intracellular signaling molecules (2). The beginning of antibiotic biosynthesis is often coordinated with processes of morphological differentiation. The characteristic Streptomyces life cycle involves the formation of a feeding substrate mycelium and subsequent development of aerial hyphae, which finally septate into spores (3). Generally, antibiotic production begins as the culture enters stationary growth in liquid culture and coincidences with the onset of morphological differentiation in agar-grown cultures (reviewed in reference 4). In many Streptomyces strains, antibiotic production is regulated by low-molecular-weight compounds, called ␥-butyrolactone autoregulators (GBLs) (5, 6). GBLs are small diffusible signaling molecules that are synthesized and gradually accumulated in a growth-dependent manner, at or near the middle of the exponential phase of Streptomyces growth, when they trigger the onset of antibiotic biosynthesis and/or morphological differentiation at nanomolar concentrations (7). Often, the GBL signal is transmitted via a hierarchical signaling cascade including pleiotropic and pathway-specific regulators, which all together control the antibiotic production: when the GBL concentration reaches a critical level, the signal is transmitted into the cells by binding to specific cytoplasmic receptor proteins, the GBL receptors (7). GBL receptors belong to the TetR family of transcriptional regulators (8). In the absence of the corresponding ligand, the GBL receptor binds to conserved AT-rich, partially palindromic sequences (9), the so-called "ARE" sequences (autoregulatory element) (10), within the promoter regions of its target genes and thereby represses the transcription of these genes. By binding of the GBLs to their receptors, the latter undergo a conformational change and dissociate from the target DNA, allowing expression of the derepressed genes (11). Predominantly, targets of GBL receptors are transcriptional regulatory genes, such as TetR and SARP (Streptomyce...

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Section: Discussionmentioning

confidence: 75%

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Mast

Guezguez

Handel

et al. 2015

Appl Environ Microbiol

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“…Like ActII-ORF4 and RedD, many other SARPs are less than 300 residues long, and some of these have been shown, mainly by mutant phenotypes, to function as pathway-specific activators, including CcaR (cephamycin-clavulanic acid supercluster in S. clavuligerus) (216), DnrI (daunorubicin biosynthesis in S. peucetius) (218,224), Aur1PR2 and Aur1PR3 (auricin biosynthesis in S. aureofaciens) (225), TylS and TylT (which activate the transcription of the tylosin CSR gene tylR in S. fradiae) (226), FdmR1 (fredericamycin biosynthesis in S. griseus) (219), ThnU (cephamycin C biosynthesis in Streptomyces cattleya) (227), SrrY and SrrZ (lankamycin biosynthetic regulatory cascade in Streptomyces rochei) (228), and VlmI (valanimycin biosynthesis in Streptomyces viridifaciens) (217). These ActII-ORF4-like SARPs are referred to here as "small SARPs."…”

Section: A Survey Of Sarpsmentioning

confidence: 99%

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Liu

Chater

Chandra

et al. 2013

Microbiol Mol Biol Rev

594

536

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SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor , the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.

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“…1) are another pair of antibiotics that are produced by a single organism, Streptomyces rochei. Their genes for production are harbored in a large plasmid pSLA2-L (8)(9)(10). This dual production hints that their mode of action may also be synergistic.…”

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confidence: 99%

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Belousoff

Shapira

Bashan

et al. 2011

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

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The structures of the large ribosomal subunit of Deinococcus radiodurans (D50S) in complex with the antibiotic lankamycin (3.2 Å) and a double antibiotic complex of lankamycin and lankacidin C (3.45 Å) have been determined, in continuation of previous crystallographic studies on lankacidin-D50S complex. These two drugs have been previously reported to inhibit ribosomal function with mild synergistic effect. Lankamycin, a member of the macrolide family, binds in a similar manner to erythromycin. However, when in complex with lankacidin, lankamycin is located so that it can form interactions with lankacidin in the adjacent ribosomal binding site. When compared to the well-documented synergistic antibiotics, Streptogramins A and B, the pair of lankacidin and lankamycin bind in similar sites, the peptidyl transferase center and nascent peptide exit tunnel, respectively. Herein, we discuss the structural basis for antibiotic synergism and highlight the key factors involved in ribosomal inhibition.protein exit tunnel | ribosomes

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Regulation of Lankamycin Biosynthesis inStreptomyces rocheiby Two SARP Genes,srrYandsrrZ

Cited by 43 publications

References 31 publications

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

A Complex Signaling Cascade Governs Pristinamycin Biosynthesis in Streptomyces pristinaespiralis

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

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