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Microbial Hormones as a Master Switch for Secondary Metabolism in Streptomyces

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Abstract

The genus Streptomyces can produce a wide variety of secondary metabolites, including antibiotics and other biologically active substances. These compounds are important starting scaffolds for the development of antibiotics, anthelminthic agents, anticancer agents, and immunosuppressants. Genome sequencing of some Streptomyces species has revealed that every Streptomyces strain has the potential to produce dozens of secondary metabolites, but only a fraction of these putative secondary metabolites are produced under standard fermentation conditions. Therefore, genetic approaches to engineering regulation are innovative ways to stimulate the expression of otherwise silent secondary metabolite gene clusters. In many Streptomyces species, γ-butyrolactone signaling molecules are used as a microbial hormone to induce secondary metabolite production. A-factor (2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) is a representative γ-butyrolactone that triggers both morphological development and production of secondary metabolites, including streptomycin in Streptomyces griseus. Here, the A-factor regulatory cascade was reviewed with some results of our recent genome-wide analysis. Disruption of arpA, encoding the A-factor receptor protein ArpA, resulted in overproduction of streptomycin. Enhanced production of secondary metabolites by gene disruption of arpA homologues was also reported for other Streptomyces species. In addition, two other methods for the induction of secondary metabolite formation in Streptomyces are briefly described. New low molecular weight signaling molecules involved in the induction of secondary metabolite formation are also briefly described.

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References

  • Arakawa K, Tsuda N, Taniguchi A, Kinashi H (2012) The butenolide signaling molecules SRB1 and SRB2 induce lankacidin and lankamycin production in Streptomyces rochei. ChemBioChem 13:1447–1457

    Article  CAS  PubMed  Google Scholar 

  • Bentley SD, Chater KF, Cerdeño-Tárraga AM et al (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature (Lond) 417:141–147

    Article  Google Scholar 

  • Bode HB, Müller R (2006) Analysis of myxobacterial secondary metabolism goes molecular. J Ind Microbiol Biotechnol 33:577–588

    Article  CAS  PubMed  Google Scholar 

  • Choi SU, Lee CK, Hwang YI, Kinoshita H, Nihira T (2004) Cloning and functional analysis by gene disruption of a gene encoding a gamma-butyrolactone autoregulator receptor from Kitasatospora setae. J Bacteriol 186:3423–3430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Corre C, Song L, O’Rourke S, Chater KF, Challis GL (2008) 2-Alkyl-4-hydroxymethylfuran-3-carboxylic acids, antibiotic production inducers discovered by Streptomyces coelicolor genome mining. Proc Natl Acad Sci USA 105:17510–17515

    Article  CAS  PubMed  Google Scholar 

  • Galagan JE, Calvo SE, Borkovich KA et al (2003) The genome sequence of the filamentous fungus Neurospora crassa. Nature (Lond) 422:859–868

    Article  CAS  Google Scholar 

  • Hara H, Ohnishi Y, Horinouchi S (2009) DNA microarray analysis of global gene regulation by A-factor in Streptomyces griseus. Microbiology 155:2197–2210

    Article  CAS  PubMed  Google Scholar 

  • Higo A, Horinouchi S, Ohnishi Y (2011) Strict regulation of morphological differentiation and secondary metabolism by a positive feedback loop between two global regulators AdpA and BldA in Streptomyces griseus. Mol Microbiol 81:1607–1622

    Article  CAS  PubMed  Google Scholar 

  • Higo A, Hara H, Horinouchi S, Ohnishi Y (2012) Genome-wide distribution of AdpA, a global regulator for secondary metabolism and morphological differentiation in Streptomyces, revealed the extent and complexity of the AdpA regulatory network. DNA Res 19:259–273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hirano S, Kato JY, Ohnishi Y, Horinouchi S (2006) Control of the Streptomyces subtilisin inhibitor gene by AdpA in the A-factor regulatory cascade in Streptomyces griseus. J Bacteriol 188:6207–6216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Horinouchi S (2002) A microbial hormone, A-factor, as a master switch for morphological differentiation and secondary metabolism in Streptomyces griseus. Front Biosci 7:d2045–d2057

    Article  CAS  PubMed  Google Scholar 

  • Horinouchi S (2007) Mining and polishing of the treasure trove in the bacterial genus Streptomyces. Biosci Biotechnol Biochem 71:283–299

    Article  CAS  PubMed  Google Scholar 

  • Horinouchi S, Beppu T (1992) Autoregulatory factors and communication in actinomycetes. Annu Rev Microbiol 46:377–398

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Kato JY, Suzuki A, Yamazaki H, Ohnishi Y, Horinouchi S (2002) Control by A-factor of a metalloendopeptidase gene involved in aerial mycelium formation in Streptomyces griseus. J Bacteriol 184:6016–6025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kato JY, Miyahisa I, Mashiko M, Ohnishi Y, Horinouchi S (2004) A single target is sufficient to account for the biological effects of the A-factor receptor protein of Streptomyces griseus. J Bacteriol 186:2206–2211

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kato JY, Chi WJ, Ohnishi Y, Hong SK, Horinouchi S (2005a) Transcriptional control by A-factor of two trypsin genes in Streptomyces griseus. J Bacteriol 187:286–295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kato JY, Ohnishi Y, Horinouchi S (2005b) Autorepression of AdpA of the AraC/XylS family, a key transcriptional activator in the A-factor regulatory cascade in Streptomyces griseus. J Mol Biol 350:12–26

    Article  CAS  PubMed  Google Scholar 

  • Kato JY, Funa N, Watanabe H, Ohnishi Y, Horinouchi S (2007) Biosynthesis of gamma-butyrolactone autoregulators that switch on secondary metabolism and morphological development in Streptomyces. Proc Natl Acad Sci USA 104:2378–2383

    Article  CAS  PubMed  Google Scholar 

  • Khokhlov AS, Tovarova II, Borisova LN et al (1967) The A-factor, responsible for streptomycin biosynthesis by mutant strains of Actinomyces streptomycini. Dokl Akad Nauk SSSR 177:232–235

    CAS  PubMed  Google Scholar 

  • Kieser T, Bibb MJ, Buttner MJ, Chater KF, Hopwood DA (2000) Practical Streptomyces genetics, 2nd edn. John Innes Foundation, Norwich

    Google Scholar 

  • Kitani S, Miyamoto KT, Takamatsu S et al (2011) Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis. Proc Natl Acad Sci USA 108:16410–16415

    Article  CAS  PubMed  Google Scholar 

  • Lee KM, Lee CK, Choi SU et al (2005) Cloning and in vivo functional analysis by disruption of a gene encoding the gamma-butyrolactone autoregulator receptor from Streptomyces natalensis. Arch Microbiol 184:249–257

    Article  CAS  PubMed  Google Scholar 

  • Miguélez EM, Hardisson C, Manzanal MB (1999) Hyphal death during colony development in Streptomyces antibioticus: morphological evidence for the existence of a process of cell deletion in a multicellular prokaryote. J Cell Biol 145:515–525

    Article  PubMed  Google Scholar 

  • Miyake K, Kuzuyama T, Horinouchi S, Beppu T (1990) The A-factor-binding protein of Streptomyces griseus negatively controls streptomycin production and sporulation. J Bacteriol 172:3003–3008

    CAS  PubMed Central  PubMed  Google Scholar 

  • Natsume R, Ohnishi Y, Senda T, Horinouchi S (2004) Crystal structure of a gamma-butyrolactone autoregulator receptor protein in Streptomyces coelicolor A3(2). J Mol Biol 336:409–419

    Article  CAS  PubMed  Google Scholar 

  • Ochi K (2007) From microbial differentiation to ribosome engineering. Biosci Biotechnol Biochem 71:1373–1386

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi Y, Kameyama S, Onaka H, Horinouchi S (1999) The A-factor regulatory cascade leading to streptomycin biosynthesis in Streptomyces griseus: identification of a target gene of the A-factor receptor. Mol Microbiol 34:102–111

    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, Ishikawa J, Hara H et al (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Okamoto S, Nakamura K, Nihira T, Yamada Y (1995) Virginiae butanolide binding protein from Streptomyces virginiae. Evidence that VbrA is not the virginiae butanolide binding protein and reidentification of the true binding protein. J Biol Chem 270:12319–12326

    Article  CAS  PubMed  Google Scholar 

  • Oliynyk M, Samborskyy M, Lester JB et al (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25:447–453

    Article  CAS  PubMed  Google Scholar 

  • Onaka H, Horinouchi S (1997) DNA-binding activity of the A-factor receptor protein and its recognition DNA sequences. Mol Microbiol 24:991–1000

    Article  CAS  PubMed  Google Scholar 

  • Onaka H, Ando N, Nihira T et al (1995) Cloning and characterization of the A-factor receptor gene from Streptomyces griseus. J Bacteriol 177:6083–6092

    CAS  PubMed Central  PubMed  Google Scholar 

  • Onaka H, Mori Y, Igarashi Y, Furumai T (2011) Mycolic acid-containing bacteria induce natural-product biosynthesis in Streptomyces species. Appl Environ Microbiol 77:400–406

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ramaswamy AV, Flatt PM, Edwards DJ et al (2006) The secondary metabolites and biosynthetic gene clusters of marine cyanobacteria. Applications in biotechnology. Front Mar Biotechnol 175–224

    Google Scholar 

  • Santamarta I, Pérez-Redondo R, Lorenzana LM, Martín 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

    Article  CAS  PubMed  Google Scholar 

  • Takano E (2006) Gamma-butyrolactones: Streptomyces signalling molecules regulating antibiotic production and differentiation. Curr Opin Microbiol 9:287–294

    Article  CAS  PubMed  Google Scholar 

  • Takano E, Nihira T, Hara Y et al (2000) Purification and structural determination of SCB1, a gamma-butyrolactone that elicits antibiotic production in Streptomyces coelicolor A3(2). J Biol Chem 275:11010–11016

    Article  CAS  PubMed  Google Scholar 

  • Takano E, Kinoshita H, Mersinias V 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 

  • Tomono A, Tsai Y, Ohnishi Y, Horinouchi S (2005a) Three chymotrypsin genes are members of the AdpA regulon in the A-factor regulatory cascade in Streptomyces griseus. J Bacteriol 187:6341–6353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tomono A, Tsai Y, Yamazaki H, Ohnishi Y, Horinouchi S (2005b) Transcriptional control by A-factor of strR, the pathway-specific transcriptional activator for streptomycin biosynthesis in Streptomyces griseus. J Bacteriol 187:5595–5604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Udwary DW, Zeigler L, Asolkar RN et al (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc Natl Acad Sci USA 104:10376–10381

    Article  CAS  PubMed  Google Scholar 

  • Ueda K, Miyake K, Horinouchi S, Beppu T (1993) A gene cluster involved in aerial mycelium formation in Streptomyces griseus encodes proteins similar to the response regulators of two-component regulatory systems and membrane translocators. J Bacteriol 175:2006–2016

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yamada Y, Nihira T (1998) Microbial hormones and microbial chemical ecology. In: Barton DHR, Nakanishi K (eds) Comprehensive natural products chemistry, vol 8. Elsevier, Heidelberg, pp 377–413

    Google Scholar 

  • Yamazaki H, Ohnishi Y, Horinouchi S (2000) An A-factor-dependent extracytoplasmic function sigma factor (σAdsA) that is essential for morphological development in Streptomyces griseus. J Bacteriol 182:4596–4605

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamazaki H, Ohnishi Y, Horinouchi S (2003a) Transcriptional switch-on of ssgA by A-factor, which is essential for spore septum formation in Streptomyces griseus. J Bacteriol 185:1273–1283

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamazaki H, Takano Y, Ohnishi Y, Horinouchi S (2003b) amfR, an essential gene for aerial mycelium formation, is a member of the AdpA regulon in the A-factor regulatory cascade in Streptomyces griseus. Mol Microbiol 50:1173–1187

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Yasuo Ohnishi .

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Tezuka, T., Ohnishi, Y. (2014). Microbial Hormones as a Master Switch for Secondary Metabolism in Streptomyces . In: Anazawa, H., Shimizu, S. (eds) Microbial Production. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54607-8_16

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