Skip to main content
Log in

Transcriptomic studies of phosphate control of primary and secondary metabolism in Streptomyces coelicolor

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Phosphate controls the biosynthesis of many classes of secondary metabolites that belong to different biosynthetic groups, indicating that phosphate control is a general mechanism governing secondary metabolism. We refer in this article to the molecular mechanisms of regulation, mediated by the two-component system PhoR–PhoP, of the primary metabolism and the biosynthesis of antibiotics. The two-component PhoR–PhoP system is conserved in all Streptomyces and related actinobacteria sequenced so far, and involves a third component PhoU that modulates the signal transduction cascade. The PhoP DNA-binding sequence is well characterized in Streptomyces coelicolor. It comprises at least two direct repeat units of 11 nt, the first seven of which are highly conserved. Other less conserved direct repeats located adjacent to the core ones can also be bound by PhoP through cooperative protein–protein interactions. The phoRphoP operon is self-activated and requires phosphorylated PhoP to mediate the full response. About 50 up-regulated PhoP-dependent genes have been identified by comparative transcriptomic studies between the parental S. coelicolor M145 and the ΔphoP mutant strains. The PhoP regulation of several of these genes has been studied in detail using EMSA and DNase I footprinting studies as well as in vivo expression studies with reporter genes and RT-PCR transcriptomic analyses.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ahlert J, Distler J, Mansouri K, Piepersberg W (1997) Identification of stsC, the gene encoding the L-glutamine:scyllo-inosose aminotransferase from streptomycin-producing streptomycetes. Arch Microbiol 168:102–113

    Article  CAS  Google Scholar 

  • Allen MP, Zumbrennen KB, McCleary WR (2001) Genetic evidence that the alpha5 helix of the receiver domain of PhoB is involved in interdomain interactions. J Bacteriol 183:2204–2211

    Article  CAS  Google Scholar 

  • Apel AK, Sola-Landa A, Rodríguez-García A, Martín JF (2007) Phosphate control of phoA, phoC and phoD gene expression in Streptomyces coelicolor reveals significant differences in binding of PhoP to their promoter regions. Microbiology 153:3527–3537

    Article  CAS  Google Scholar 

  • Bibb MJ (2005) Regulation of secondary metabolism in streptomycetes. Curr Opin Microbiol 8:208–215

    Article  CAS  Google Scholar 

  • Birck C, Chen Y, Hulett FM, Samama JP (2003) The crystal structure of the phosphorylation domain in PhoP reveals a functional tandem association mediated by an asymmetric interface. J Bacteriol 185:254–261

    Article  CAS  Google Scholar 

  • Blanco AG, Solà M, Gomis-Rüth FX, Coll M (2002) Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator. Structure 10:701–713

    Article  CAS  Google Scholar 

  • Browning DF, Busby SJ (2004) The regulation of bacterial transcription initiation. Nat Rev Microbiol 2:57–65

    Article  CAS  Google Scholar 

  • Brzoska P, Boos W (1989) The ugp-encoded glycerophosphoryldiester phosphodiesterase, a transport-related enzyme of Escherichia coli. FEMS Microbiol Rev 5:115–124

    Article  CAS  Google Scholar 

  • Chen Y, Birck C, Samama JP, Hulett FM (2003) Residue R113 is essential for PhoP dimerization and function: a residue buried in the asymmetric PhoP dimer interface determined in the PhoPN three-dimensional crystal structure. J Bacteriol 185:262–273

    Article  CAS  Google Scholar 

  • Cheng YR, Hauck L, Demain AL (1995) Phosphate, ammonium, magnesium and iron nutrition of Streptomyces hygroscopicus with respect to rapamycin biosynthesis. J Ind Microbiol 14:424–427

    Article  CAS  Google Scholar 

  • Cheung J, Hendrickson WA (2010) Sensor domains of two-component regulatory systems. Curr Opin Microbiol 13:116–123

    Article  CAS  Google Scholar 

  • Chouayekh H, Virolle M-J (2002) The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans. Mol Microbiol 43:919–930

    Article  CAS  Google Scholar 

  • Dekeva ML, Titus JA, Strohl WR (1985) Nutrient effects on anthracycline production by Streptomyces peucetius in a defined medium. Can J Microbiol 31:287–294

    Article  Google Scholar 

  • Díaz M, Esteban A, Fernández-Abalos JM, Santamaría RI (2005) The high-affinity phosphate-binding protein PstS is accumulated under high fructose concentrations and mutation of the corresponding gene affects differentiation in Streptomyces lividans. Microbiology 151:2583–2592

    Article  Google Scholar 

  • Doull JL, Vining LC (1990) Nutritional control of actinorhodin production by Streptomyces coelicolor A3(2): suppressive effects of nitrogen and phosphate. Appl Microbiol Biotechnol 32:449–454

    Article  CAS  Google Scholar 

  • Eder S, Liu W, Hulett FM (1999) Mutational analysis of the phoD promoter in Bacillus subtilis: implications for PhoP binding and promoter activation of Pho regulon promoters. J Bacteriol 181:2017–2025

    CAS  Google Scholar 

  • Ellison DW, McCleary WR (2000) The unphosphorylated receiver domain of PhoB silences the activity of its output domain. J Bacteriol 182:6592–6597

    Article  CAS  Google Scholar 

  • Fabret C, Feher VA, Hoch JA (1999) Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J Bacteriol 181:1975–1983

    CAS  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

    Article  CAS  Google Scholar 

  • Galperin MY (2010) Diversity of structure and function of response regulator output domains. Curr Opin Microbiol 13:150–159

    Article  CAS  Google Scholar 

  • Ghorbel S, Kormanec J, Artus A, Virolle MJ (2006a) Transcriptional studies and regulatory interactions between the phoR-phoP operon and the phoU, mtpA, and ppk genes of Streptomyces lividans TK24. J Bacteriol 188:677–686

    Article  CAS  Google Scholar 

  • Ghorbel S, Smirnov A, Chouayekh H, Sperandio B, Esnault C, Kormanec J, Virolle M-J (2006b) Regulation of ppk expression and in vivo function of Ppk in Streptomyces lividans TK24. J Bacteriol 188:6269–6276

    Article  CAS  Google Scholar 

  • Hobbs G, Frazer CM, Gardner DCJ, Flett F, Oliver SG (1990) Pigmented antibiotic production by Streptomyces coelicolor A3(2): kinetics and the influence of nutrients. J Gen Microbiol 136:2291–2296

    CAS  Google Scholar 

  • Hoi LT, Voigt B, Jürgen B, Ehrenreich A, Gottschalk G, Evers S, Feesche J, Maurer K-H, Hecker M, Schweder T (2006) The phosphate-starvation response of Bacillus licheniformis. Proteomics 6:3582–3601

    Article  CAS  Google Scholar 

  • Hutchings MI, Hoskisson PA, Chandra G, Buttner MJ (2004) Sensing and responding to diverse extracellular signals? Analysis of the sensor kinases and response regulators of Streptomyces coelicolor A3(2). Microbiology 150:2795–2806

    Article  CAS  Google Scholar 

  • Krol E, Becker A (2004) Global transcriptional analysis of the phosphate starvation response in Sinorhizobium meliloti strains 1021 and 2011. Mol Genet Genomics 272:1–17

    Article  CAS  Google Scholar 

  • Liras P, Asturias JA, Martín JF (1990) Phosphate control sequences involved in transcriptional regulation of antibiotic biosynthesis. Trends Biotechnol 8:184–189

    Article  CAS  Google Scholar 

  • Liu W, Eder S, Hulett FM (1998) Analysis of Bacillus subtilis tagAB and tagDEF expression during phosphate starvation identifies a repressor role for PhoP-P. J Bacteriol 180:753–758

    CAS  Google Scholar 

  • Lounes A, Lebrihi A, Benslimane C, Lefebvre G, Germain P (1996) Regulation of spiramycin synthesis in Streptomyces ambofaciens: effects of glucose and inorganic phosphate. Appl Microbiol Biotechnol 45:204–211

    Article  CAS  Google Scholar 

  • Makarewicz O, Dubrac S, Msadek T, Borriss R (2006) Dual role of the PhoP P response regulator: Bacillus amyloliquefaciens FZB45 phytase gene transcription is directed by positive and negative interactions with the phyC promoter. J Bacteriol 188:6953–6965

    Article  CAS  Google Scholar 

  • Manteca A, Ye J, Sánchez J, Jensen ON (2011) Phosphoproteome analysis of Streptomyces development reveals extensive protein phosphorylation accompanying bacterial differentiation. J Proteome Res 10:5481–5492

    CAS  Google Scholar 

  • Martín JF (1989) Molecular mechanism for the control by phosphate of the biosynthesis of antibiotic and secondary metabolites. In: Shapiro S (ed) Regulation of secondary metabolism in actinomycetes. CRC, Boca Raton, pp 213–236

    Google Scholar 

  • Martín JF (2004) Phosphate control of the biosynthesis of antibiotics and other secondary metabolites is mediated by the PhoR-PhoP system: an unfinished story. J Bacteriol 186:5197–5201

    Article  Google Scholar 

  • Martín JF, Demain A (1980) Control of antibiotic biosynthesis. Microbiol Rev 44:230–251

    Google Scholar 

  • Martín JF, Marcos AT, Martín A, Asturias JA, Liras P (1994) Phosphate control of antibiotic biosynthesis at the transcriptional level. In: Torriani-Gorini A, Yagil E, Silver S (eds) Phosphate in microorganisms. ASM, Washington, pp 140–147

    Google Scholar 

  • Martín JF, Gutiérrez S, Aparicio JF (2000) Secondary metabolites. In: Lederberg J (ed) Encyclopedia of microbiology, vol 4, 2nd edn. Academic, San Diego, pp 213–237

    Google Scholar 

  • Martín JF, Sola-Landa A, Santos-Beneit F, Rodríguez-García A (2011) Network mechanisms of phosphate control of primary and secondary metabolism. In: Dyson P (ed) Streptomyces: molecular biology and biotechnology. Caister Academic, Norwich, pp 137–149

    Google Scholar 

  • Martín JF, Sola-Landa A, Rodríguez-García A (2012) Two-component systems in Streptomyces. In: Gross R, Beier D (eds) Two-component systems in bacteria. Caister Academic, Würzburg, pp 315–331

  • Masuma R, Tanaka Y, Tanaka H, Omura S (1986) Production of nanaomycin and other antibiotics by phosphate-depressed fermentation using phosphate-trapping agents. J Antibiot (Tokyo) 39:1557–1564

    Article  CAS  Google Scholar 

  • Mendes MV, Tunca S, Antón N, Recio E, Sola-Landa A, Aparicio JF, Martín JF (2007) The two-component phoR-phoP system of Streptomyces natalensis: inactivation or deletion of phoP reduces the negative phosphate regulation of pimaricin biosynthesis. Metabol Engineer 9:217–227

    Article  CAS  Google Scholar 

  • Nieselt K, Battke F, Herbig A, Bruheim P, Wentzel A, Jakobsen OM, Sletta H, Alam MT, Merlo ME, Moore J, Omara WA, Morrissey ER, Juarez-Hermosillo MA, Rodríguez-García A, Nentwich M, Thomas L, Iqbal M, Legaie R, Gaze WH, Challis GL, Jansen RC, Dijkhuizen L, Rand DA, Wild DL, Bonin M, Reuther J, Wohlleben W, Smith MC, Burroughs NJ, Martín JF, Hodgson DA, Takano E, Breitling R, Ellingsen TE, Wellington EM (2010) The dynamic architecture of the metabolic switch in Streptomyces coelicolor. BMC Genomics 11:10–19

    Article  Google Scholar 

  • Perron-Savard P, De Crescenzo G, Le Moual H (2005) Dimerization and DNA binding of the Salmonella enterica PhoP response regulator are phosphorylation independent. Microbiology 151:3979–3987

    Article  CAS  Google Scholar 

  • Prágai Z, Allenby NE, O'Connor N, Dubrac S, Rapoport G, Msadek T, Harwood CR (2004) Transcriptional regulation of the phoPR operon in Bacillus subtilis. J Bacteriol 186:1182–1190

    Article  Google Scholar 

  • Pullan ST, Chandra G, Bibb MJ, Merrick M (2011) Genome-wide analysis of the role of GlnR in Streptomyces venezuelae provides new insights into global nitrogen regulation in actinomycetes. BMC Genomics 12:175–189

    Article  CAS  Google Scholar 

  • Puri-Taneja A, Paul S, Chen Y, Hulett FM (2006) CcpA causes repression of the phoPR promoter through a novel transcription start site, PA6. J Bacteriol 188:1266–1278

    Article  CAS  Google Scholar 

  • Quiquampoix H, Mousain D (2005) Enzymatic hydrolysis of organic phosphorus. In: Turner BL, Frossard E, Baldwin DS (eds) Organic phosphorus in the environment. CABI, Cambridge, pp 89–112

    Chapter  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  Google Scholar 

  • Rigali S, Titgemeyer F, Barends S, Mulder S, Thomae AW, Hopwood DA, van Wezel GP (2008) Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by Streptomyces. EMBO Rep 9:670–675

    Article  CAS  Google Scholar 

  • Rodríguez-García A, Barreiro C, Santos-Beneit F, Sola-Landa A, Martín JF (2007) Genome-wide transcriptomic and proteomic analysis of the primary response to phosphate limitation in Streptomyces coelicolor M145 and in a ∆phoP mutant. Proteomics 7:2410–2429

    Article  Google Scholar 

  • Rodríguez-García A, Sola-Landa A, Apel K, Santos-Beneit F, Martín JF (2009) Phosphate control over nitrogen metabolism in Streptomyces coelicolor: direct and indirect negative control of glnR, glnA, glnII and amtB expression by the response regulator PhoP. Nucleic Acids Res 37:3230–3242

    Article  Google Scholar 

  • Romero J, Liras P, Martín JF (1984) Dissociation of cephamycin and clavulanic acid biosynthesis in Streptomyces clavuligerus. Appl Microbiol Biotechnol 20:318–325

    Article  CAS  Google Scholar 

  • Saito N, Xu J, Hosaka T, Okamoto S, Aoki H, Bibb MJ, Ochi K (2006) EshA accentuates ppGpp accumulation and is conditionally required for antibiotic production in Streptomyces coelicolor A3(2). J Bacteriol 188:4952–4961

    Article  CAS  Google Scholar 

  • Santos-Beneit F, Rodríguez-García A, Franco-Domínguez E, Martín JF (2008) Phosphate-dependent regulation of the low- and high-affinity transport systems in the model actinomycete Streptomyces coelicolor. Microbiology 154:2356–2370

    Article  CAS  Google Scholar 

  • Santos-Beneit F, Rodríguez-García A, Sola-Landa A, Martín JF (2009a) Cross-talk between two global regulators in Streptomyces: PhoP and AfsR interact in the control of afsS, pstS and phoRP transcription. Mol Microbiol 72:53–68

    Article  CAS  Google Scholar 

  • Santos-Beneit F, Rodríguez-García A, Apel AK, Martín JF (2009b) Phosphate and carbon source regulation of two PhoP-dependent glycerophosphodiester phosphodiesterase genes of Streptomyces coelicolor. Microbiology 155:1800–1811

    Article  CAS  Google Scholar 

  • Santos-Beneit F, Rodríguez-García A, Martín JF (2011a) Complex transcriptional control of the antibiotic regulator afsS in Streptomyces: PhoP and AfsR are overlapping, competitive activators. J Bacteriol 193:2242–2251

    Article  CAS  Google Scholar 

  • Santos-Beneit F, Barriuso-Iglesias M, Fernández-Martínez LT, Martínez-Castro M, Sola-Landa A, Rodríguez-García A, Martín JF (2011b) The RNA polymerase omega factor RpoZ is regulated by PhoP and has an important role in antibiotic biosynthesis and morphological differentiation in Streptomyces coelicolor. Appl Environ Microbiol 77:7586–7594

    Article  CAS  Google Scholar 

  • Schaaf S, Bott M (2007) Target genes and DNA-binding sites of the response regulator PhoR from Corynebacterium glutamicum. J Bacteriol 189:5002–5011

    Article  CAS  Google Scholar 

  • Schneider TD (1997) Information content of individual genetic sequences. J Theor Biol 189:427–441

    Article  CAS  Google Scholar 

  • Sinha A, Gupta S, Bhutani S, Pathak A, Sarkar D (2008) PhoP-PhoP interaction at adjacent PhoP binding sites is influenced by protein phosphorylation. J Bacteriol 190:1317–1328

    Article  CAS  Google Scholar 

  • Sola-Landa A, Moura RS, Martín JF (2003) The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans. Proc Natl Acad Sci USA 100:6133–6138

    Article  CAS  Google Scholar 

  • Sola-Landa A, Rodríguez-García A, Franco-Domínguez E, Martín JF (2005) Binding of PhoP to promoters of phosphate-regulated genes in Streptomyces coelicolor: identification of PHO boxes. Mol Microbiol 56:1373–1385

    Article  CAS  Google Scholar 

  • Sola-Landa A, Rodríguez-García A, Apel AK, Martín JF (2008) Target genes and structure of the direct repeats in the DNA binding sequences of the response regulator PhoP in Streptomyces coelicolor. Nucleic Acids Res 36:1358–1368

    Article  CAS  Google Scholar 

  • Stieglitz KA, Seaton BA, Roberts MF (2001) Binding of proteolytically processed phospholipase D from Streptomyces chromofuscus to phosphatidylcholine membranes facilitates vesicle aggregation and fusion. Biochemistry 40:13954–13963

    Article  CAS  Google Scholar 

  • Suzuki S, Ferjani A, Suzuki I, Murata N (2004) The SphS-SphR two component system is the exclusive sensor for the induction of gene expression in response to phosphate limitation in Synechocystis. J Biol Chem 279:13234–13240

    Article  CAS  Google Scholar 

  • Tamegai H, Eguchi T, Kakinuma K (2002) First identification of Streptomyces genes involved in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics—genetic and evolutionary analysis of L-glutamine:2-deoxy-scyllo-inosose aminotransferase genes. J Antibiot (Tokyo) 55:1016–1018

    Article  CAS  Google Scholar 

  • Thomas L, Hodgson DA, Wentzel A, Nieselt K, Ellingsen TE, Moore J, Morrissey ER, Legaie R, The STREAM Consortium, Rodríguez-García A, Martín JF, Burroughs NJ, Wellington EM, Smith MC (2012) Metabolic switches and adaptations deduced from the proteomes of Streptomyces coelicolor wild type and phoP mutant grown in batch culture. Mol Cell Proteomics 11:M111.013797

    Article  Google Scholar 

  • Tiffert Y, Supra P, Wurm R, Wohlleben W, Wagner R, Reuther J (2008) The Streptomyces coelicolor GlnR regulon: identification of new GlnR targets and evidence for a central role of GlnR in nitrogen metabolism in actinomycetes. Mol Microbiol 67:861–880

    Article  CAS  Google Scholar 

  • Uesugi Y, Hatanaka T (2009) Phospholipase D mechanism using Streptomyces PLD. Biochim Biophys Acta 1791:962–969

    CAS  Google Scholar 

  • VanBogelen RA, Olson ER, Wanner BL, Neidhardt FC (1996) Global analysis of proteins synthesized during phosphorus restriction in Escherichia coli. J Bacteriol 178:4344–4366

    CAS  Google Scholar 

  • Vining LC (1992) Secondary metabolism, inventive evolution and biochemical diversity—a review. Gene 115:135–140

    Article  CAS  Google Scholar 

  • Wanner BL (1996) Phosphorus assimilation and control of the phosphate regulon. In: Neidhardt FC, Ingraham JL, Lin ECC, Low KB, Magasanik B, Reznikoff WS, Riley M, Schaechter M, Umbarger HE (eds) Escherichia coli and Salmonella, 2nd edn. American Society for Microbiology, Washington, pp 1357–1381

    Google Scholar 

  • Wösten MM, Parker CT, van Mourik A, Guilhabert MR, van Dijk L, van Putten JP (2006) The Campylobacter jejuni PhosS/PhosR operon represents a non-classical phosphate-sensitive two-component system. Mol Microbiol 62:278–291

    Article  Google Scholar 

  • Wray LV, Fisher SH (1993) The Streptomyces coelicolor glnR gene encodes a protein similar to other bacterial response regulators. Gene 130:145–150

    Article  CAS  Google Scholar 

  • Yamane T, Okamura H, Ikeguchi M, Nishimura Y, Kidera A (2008) Water-mediated interactions between DNA and PhoB DNA-binding/transactivation domain: NMR-restrained molecular dynamics in explicit water environment. Proteins 71:1970–1983

    Article  CAS  Google Scholar 

  • Yang H, Roberts MF (2002) Cloning, overexpression, and characterization of a bacterial Ca2+-dependent phospholipase D. Protein Sci 11:2958–2968

    Article  CAS  Google Scholar 

  • Yuan ZC, Zaheer R, Morton R, Finan TM (2006) Genome prediction of PhoB regulated promoters in Sinorhizobium meliloti and twelve proteobacteria. Nucleic Acids Res 34:2686–2697

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the ERA-NET SysMO STREAM grant (GEN2006-27745-E/SYS) of the EU and by the CICYT grants BIO2010-16094 and ERA-IB-2 (PIM2010EEI-00667) of the Ministry of Economy and Competitiveness of Spain.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Juan F. Martín.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martín, J.F., Santos-Beneit, F., Rodríguez-García, A. et al. Transcriptomic studies of phosphate control of primary and secondary metabolism in Streptomyces coelicolor . Appl Microbiol Biotechnol 95, 61–75 (2012). https://doi.org/10.1007/s00253-012-4129-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-012-4129-6

Keywords

Navigation