Skip to main content
SpringerLink
Log in

NdgR, an IclR-like regulator involved in amino-acid-dependent growth, quorum sensing, and antibiotic production in Streptomyces coelicolor

  • Applied Genetics and Molecular Biotechnology
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

NdgR (regulator for nitrogen source-dependent growth and antibiotic production), an IclR-like regulator, has been initially identified as a binding protein to the promoters of doxorubicin biosynthetic genes in Streptomcyes peucetius by DNA affinity capture assay method. NdgR is well conserved throughout the Streptomcyes species and many other bacteria such as Mycobacteria and Corynebacteria. In Streptomcyes coelicolor, ndgR deletion mutant showed slow cell growth and defects in differentiation and enhances the production of actinorhodin (ACT) in minimal media containing certain amino acids where wild-type strain could not produce ACT. Although deletion mutant of ndgR showed different antibiotic production in minimal media containing Leu or Gln, it only showed reduced mRNA expression levels of the genes involved in leucine metabolism. Neither NdgR-dependent expression of glnA nor direct binding of NdgR protein to glnA, glnII, and glnR promoters was observed. However, ScbR, which is governed by NdgR shown by gel mobility shift assay, binds to promoter of glnR, suggesting indirect regulation of glutamine metabolism by NdgR. NdgR protein binds to intergenic region of ndgR–leuC, and scbR–scbA involved in γ-butyrolactone. Two-dimensional gel analysis has shown a global effect of ndgR deletion in protein expression, including up-regulated proteins involved in ACT synthesis and down-regulation of chaperones such as GroEL, GroES, and DnaK. These results suggest a global regulatory role for NdgR in amino acid metabolisms, quorum sensing, morphological changes, antibiotic production, and expression of chaperonines in S. coelicolor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Alon U (2007) An introduction to systems biology: design principles of biological circuits. Chapman & Hall, London, p 29

    Google Scholar 

  • Bentley SD et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147

    Article  PubMed  Google Scholar 

  • Bibb M (1996) 1995 Colworth Prize Lecture. The regulation of antibiotic production in Streptomyces coelicolor A3(2). Microbiology 142(Pt 6):1335–1344

    Article  CAS  PubMed  Google Scholar 

  • Brune I et al (2007) The IclR-type transcriptional repressor LtbR regulates the expression of leucine and tryptophan biosynthesis genes in the amino acid producer Corynebacterium glutamicum. J Bacteriol 189:2720–2733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chater KF (2001) Regulation of sporulation in Streptomyces coelicolor A3(2): a checkpoint multiplex? Curr Opin Microbiol 4:667–673

    Article  CAS  PubMed  Google Scholar 

  • Chater KF, Horinouchi S (2003) Signalling early developmental events in two highly diverged Streptomyces species. Mol Microbiol 48:9–15

    Article  CAS  PubMed  Google Scholar 

  • Claessen D, de Jong W, Dijkhuizen L, Wosten HA (2006) Regulation of Streptomyces development: reach for the sky!. Trends Microbiol 14:313–319

    Article  CAS  PubMed  Google Scholar 

  • Craster HL, Potter CA, Baumberg S (1999) End-product control of expression of branched-chain amino acid biosynthesis genes in Streptomyces coelicolor A3(2): paradoxical relationships between DNA sequence and regulatory phenotype. Microbiology 145(Pt 9):2375–2384

    Article  CAS  PubMed  Google Scholar 

  • Fink D, Weissschuh N, Reuther J, Wohlleben W, Engels A (2002) Two transcriptional regulators GlnR and GlnRII are involved in regulation of nitrogen metabolism in Streptomyces coelicolor A3(2). Mol Microbiol 46:331–347

    CAS  PubMed  Google Scholar 

  • Gramajo HC, Takano E, Bibb MJ (1993) Stationary-phase production of the antibiotic actinorhodin in Streptomyces coelicolor A3(2) is transcriptionally regulated. Mol Microbiol 7:837–845

    Article  CAS  PubMed  Google Scholar 

  • Gust B, Challis GL, Fowler K, Kieser T, Chater KF (2003) PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc Natl Acad Sci USA 100:1541–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hillerich B, Westpheling J (2006) A new GntR family transcriptional regulator in streptomyces coelicolor is required for morphogenesis and antibiotic production and controls transcription of an ABC transporter in response to carbon source. J Bacteriol 188:7477–7487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopwood DA (1999) Forty years of genetics with Streptomyces: from in vivo through in vitro to in silico. Microbiology 145(Pt 9):2183–2202

    Article  CAS  PubMed  Google Scholar 

  • Horinouchi S, Hara O, Beppu T (1983) Cloning of a pleiotropic gene that positively controls biosynthesis of A-factor, actinorhodin, and prodigiosin in Streptomyces coelicolor A3(2) and Streptomyces lividans. J Bacteriol 155:1238–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horinouchi S et al (1990) Primary structure of AfsR, a global regulatory protein for secondary metabolite formation in Streptomyces coelicolor A3(2). Gene 95:49–56

    Article  CAS  PubMed  Google Scholar 

  • Hoskisson PA, Rigali S, Fowler K, Findlay KC, Buttner MJ (2006) DevA, a GntR-like transcriptional regulator required for development in Streptomyces coelicolor. In: J Bacteriol, pp 5014–5023

  • Hsiao NH et al (2007) ScbA from Streptomyces coelicolor A3(2) has homology to fatty acid synthases and is able to synthesize gamma-butyrolactones. Microbiology 153:1394–1404

    Article  CAS  PubMed  Google Scholar 

  • Huang J et al (2005) Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor. Mol Microbiol 58:1276–1287

    Article  CAS  PubMed  Google Scholar 

  • Hung TV, Ishida K, Parajuli N, Liou K, Lee HC, Sohng JK (2006) Enhanced clavulanic acid production in Streptomyces clavuligerus NRRL3585 by overexpression of regulatory genes. Biotechnol Bioprocess Eng 11:116–120

    Article  CAS  Google Scholar 

  • Hutchinson CR, Colombo AL (1999) Genetic engineering of doxorubicin production in Streptomyces peucetius: a review. J Ind Microbiol Biotechnol 23:647–652

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H et al (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531

    Article  PubMed  Google Scholar 

  • Kelemen GH, Buttner MJ (1998) Initiation of aerial mycelium formation in Streptomyces. Curr Opin Microbiol 1:656–662

    Article  CAS  PubMed  Google Scholar 

  • Kieser T, Bibb MJ, Buttner MJ, Chater K, Hopwood DA (2000) Practical Streptomyces genetics. John Innes Centre, Norwich Research Park, Colney, Norwich, UK

    Google Scholar 

  • Kim HS et al (2004) Cloning and characterization of a gene encoding the gamma-butyrolactone autoregulator receptor from Streptomyces clavuligerus. Arch Microbiol 182:44–50

    Article  CAS  PubMed  Google Scholar 

  • Lee EJ et al (2005) A master regulator sigmaB governs osmotic and oxidative response as well as differentiation via a network of sigma factors in Streptomyces coelicolor. Mol Microbiol 57:1252–1264

    Article  CAS  PubMed  Google Scholar 

  • Li W et al (2006) Identification of a gene negatively affecting antibiotic production and morphological differentiation in Streptomyces coelicolor A3(2). J Bacteriol 188:8368–8375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liras P, Gomez-Escribano JP, Santamarta I (2008) Regulatory mechanisms controlling antibiotic production in Streptomyces clavuligerus. J Ind Microbiol Biotechnol 35(7):667–676

    Article  CAS  PubMed  Google Scholar 

  • McKenzie NL, Nodwell JR (2007) Phosphorylated AbsA2 negatively regulates antibiotic production in Streptomyces coelicolor through interactions with pathway-specific regulatory gene promoters. J Bacteriol 189:5284–5292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molina-Henares AJ, Krell T, Eugenia Guazzaroni M, Segura A, Ramos JL (2006) Members of the IclR family of bacterial transcriptional regulators function as activators and/or repressors. FEMS Microbiol Rev 30:157–186

    Article  CAS  PubMed  Google Scholar 

  • Nicholas HB Jr, Ropelewski AJ, Deerfield DW 2nd (2002) Strategies for multiple sequence alignment. Biotechniques 32:572–574 576, 578 passim

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi Y, Yamazaki H, Kato JY, Tomono A, Horinouchi S (2005) AdpA, a central transcriptional regulator in the A-factor regulatory cascade that leads to morphological development and secondary metabolism in Streptomyces griseus. Biosci Biotechnol Biochem 69:431–439

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi Y et al (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onaka H, Nakagawa T, Horinouchi S (1998) Involvement of two A-factor receptor homologues in Streptomyces coelicolor A3(2) in the regulation of secondary metabolism and morphogenesis. Mol Microbiol 28:743–753

    Article  CAS  PubMed  Google Scholar 

  • Parajuli N, Basnet DB, Chan Lee H, Sohng JK, Liou K (2004) Genome analyses of Streptomyces peucetius ATCC 27952 for the identification and comparison of cytochrome P450 complement with other Streptomyces. Arch Biochem Biophys 425:233–241

    Article  CAS  PubMed  Google Scholar 

  • Park SS, Ko BJ, Kim BG (2005) Mass spectrometric screening of transcriptional regulators using DNA affinity capture assay. Anal Biochem 344:152–154

    Article  CAS  PubMed  Google Scholar 

  • Reuther J, Wohlleben W (2007) Nitrogen metabolism in Streptomyces coelicolor: transcriptional and post-translational regulation. J Mol Microbiol Biotechnol 12:139–146

    Article  CAS  PubMed  Google Scholar 

  • Rexer HU, Schaberle T, Wohlleben W, Engels A (2006) Investigation of the functional properties and regulation of three glutamine synthetase-like genes in Streptomyces coelicolor A3(2). Arch Microbiol 186:447–458

    Article  CAS  PubMed  Google Scholar 

  • Rigali S et al (2006) The sugar phosphotransferase system of Streptomyces coelicolor is regulated by the GntR-family regulator DasR and links N-acetylglucosamine metabolism to the control of development. Mol Microbiol 61:1237–1251

    Article  CAS  PubMed  Google Scholar 

  • Santamarta I, Perez-Redondo R, Lorenzana LM, Martin JF, Liras P (2005) Different proteins bind to the butyrolactone receptor protein ARE sequence located upstream of the regulatory ccaR gene of Streptomyces clavuligerus. Mol Microbiol 56:824–835

    CAS  PubMed  Google Scholar 

  • Santamarta I, Lopez-Garcia MT, Perez-Redondo R, Koekman B, Martin JF, Liras P (2007) Connecting primary and secondary metabolism: AreB, an IclR-like protein, binds the ARE(ccaR) sequence of S. clavuligerus and modulates leucine biosynthesis and cephamycin C and clavulanic acid production. Mol Microbiol 66:511–524

    Article  CAS  PubMed  Google Scholar 

  • Takano E, Gramajo HC, Strauch E, Andres N, White J, Bibb MJ (1992) Transcriptional regulation of the redD transcriptional activator gene accounts for growth-phase-dependent production of the antibiotic undecylprodigiosin in Streptomyces coelicolor A3(2). Mol Microbiol 6:2797–2804

    Article  CAS  PubMed  Google Scholar 

  • Takano E, Chakraburtty R, Nihira T, Yamada Y, Bibb MJ (2001) A complex role for the gamma-butyrolactone SCB1 in regulating antibiotic production in Streptomyces coelicolor A3(2). Mol Microbiol 41:1015–1028

    Article  CAS  PubMed  Google Scholar 

  • Takano E et al (2003) A rare leucine codon in adpA is implicated in the morphological defect of bldA mutants of Streptomyces coelicolor. Mol Microbiol 50:475–486

    Article  CAS  PubMed  Google Scholar 

  • Takano E et al (2005) A bacterial hormone (the SCB1) directly controls the expression of a pathway-specific regulatory gene in the cryptic type I polyketide biosynthetic gene cluster of Streptomyces coelicolor. Mol Microbiol 56:465–479

    Article  CAS  PubMed  Google Scholar 

  • Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Wezel GP, White J, Young P, Postma PW, Bibb MJ (1997) Substrate induction and glucose repression of maltose utilization by Streptomyces coelicolor A3(2) is controlled by malR, a member of the lacl-galR family of regulatory genes. Mol Microbiol 23:537–549

    Article  PubMed  Google Scholar 

  • van Wezel GP, van der Meulen J, Kawamoto S, Luiten RG, Koerten HK, Kraal B (2000) ssgA is essential for sporulation of Streptomyces coelicolor A3(2) and affects hyphal development by stimulating septum formation. J Bacteriol 182:5653–5662

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang YH et al (2005) Novel method for detection of butanolides in Streptomyces coelicolor culture broth, using a His-tagged receptor (ScbR) and mass spectrometry. Appl Environ Microbiol 71:5050–5055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Yao Y, Liu Y, Jiao R, Jiang W, Zhao GP (2007) A complex role of Amycolatopsis mediterranei GlnR in nitrogen metabolism and related antibiotics production. Arch Microbiol 188:89–96

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank John Innes Center for providing the cosmid library and wish to acknowledge the Engineering Research Institute, Seoul National University. This work was partially supported by a grant funded by the Korea government (MOST; No. R0A-2007-000-10007-0) and a grant (Code # KRF-2005-005-J16002) from Korea Research Foundation, Republic of Korea.

Author information

Authors and Affiliations

  1. School of Chemical and Biological Engineering, Seoul National University, Seoul, South Korea

    Yung-Hun Yang, Eunjung Song, Eun-Jung Kim, Woo-Seong Kim, Sung-Soo Park, Ji-Sook Hahn & Byung-Gee Kim

  2. Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul, South Korea

    Kwangwon Lee, Ji-Sook Hahn & Byung-Gee Kim

  3. Institute of Bioengineering, Seoul National University, Seoul, South Korea

    Yung-Hun Yang, Eunjung Song, Eun-Jung Kim, Kwangwon Lee, Woo-Seong Kim, Sung-Soo Park, Ji-Sook Hahn & Byung-Gee Kim

Authors
  1. Yung-Hun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eunjung Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eun-Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kwangwon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Woo-Seong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sung-Soo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ji-Sook Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Byung-Gee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byung-Gee Kim.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supple. Fig. 1

Multiple alignment of NdgR homologues in various species (DOC 286 kb)

Supplementary Table 1

Strains, plasmids, and primers (DOC 105 kb)

Supplementary Table 2

The results of DNA affinity capture assay with various promoters from S. peucetius (DOC 31 kb)

Supplementary Table 3

NdgR regulators in various species (DOC 41 kb)

Supplementary Table 4

Sequences of newly shown NdgR homologues (DOC 27 kb)

Supplementary Table 5

Identified proteins by 2-D gel analysis (DOC 106 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, YH., Song, E., Kim, EJ. et al. NdgR, an IclR-like regulator involved in amino-acid-dependent growth, quorum sensing, and antibiotic production in Streptomyces coelicolor . Appl Microbiol Biotechnol 82, 501–511 (2009). https://doi.org/10.1007/s00253-008-1802-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-008-1802-x

Keywords

Search

Navigation