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Regulatory genes and their roles for improvement of antibiotic biosynthesis in Streptomyces

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Abstract

The numerous secondary metabolites in Streptomyces spp. are crucial for various applications. For example, cephamycin C is used as an antibiotic, and avermectin is used as an insecticide. Specifically, antibiotic yield is closely related to many factors, such as the external environment, nutrition (including nitrogen and carbon sources), biosynthetic efficiency and the regulatory mechanisms in producing strains. There are various types of regulatory genes that work in different ways, such as pleiotropic (or global) regulatory genes, cluster-situated regulators, which are also called pathway-specific regulatory genes, and many other regulators. The study of regulatory genes that influence antibiotic biosynthesis in Streptomyces spp. not only provides a theoretical basis for antibiotic biosynthesis in Streptomyces but also helps to increase the yield of antibiotics via molecular manipulation of these regulatory genes. Currently, more and more emphasis is being placed on the regulatory genes of antibiotic biosynthetic gene clusters in Streptomyces spp., and many studies on these genes have been performed to improve the yield of antibiotics in Streptomyces. This paper lists many antibiotic biosynthesis regulatory genes in Streptomyces spp. and focuses on frequently investigated regulatory genes that are involved in pathway-specific regulation and pleiotropic regulation and their applications in genetic engineering.

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References

  • Aigle B, Pang X, Decaris B, Leblond P (2005) Involvement of AlpV, a new member of the Streptomyces antibiotic regulatory protein family, in regulation of the duplicated type II polyketide synthase alp gene cluster in Streptomyces ambofaciens. J Bacteriol 187:2491–2500. doi:10.1128/jb.187.7.2491-2500.2005

    Article  CAS  Google Scholar 

  • Antón N, Mendes MV, Martín JF, Aparicio JF (2004) Identification of PimR as a positive regulator of pimaricin biosynthesis in Streptomyces natalensis. J Bacteriol 186:2567–2575. doi:10.1128/jb.186.9.2567-2575.2004

    Article  CAS  Google Scholar 

  • Arakawa K, Mochizuki S, Yamada K, Noma T, Kinashi H (2007) γ-Butyrolactone autoregulator-receptor system involved in lankacidin and lankamycin production and morphological differentiation in Streptomyces rochei. Microbiology 153:1817–1827. doi:10.1099/mic.0.2006/002170-0

    Article  CAS  Google Scholar 

  • Arias P, Fernández-Moreno MA, Malpartida F (1999) Characterization of the pathway-specific positive transcriptional regulator for actinorhodin biosynthesis in Streptomyces coelicolor A3(2) as a DNA-binding protein. J Bacteriol 181:6958–6968

    CAS  Google Scholar 

  • Atsushi M, Soon-Kwang H, Hiroshi I, Sueharu H, Teruhiko B (1994) Phosphorylation of the AfsR protein involved in secondary metabolism in Streptomyces species by a eukary otic-type protein kinase. Gene 146:47–56. doi:10.1016/0378-1119(94)90832-X

    Article  Google Scholar 

  • Bai L et al (2006) Functional analysis of the validamycin biosynthetic gene cluster and engineered production of validoxylamine A. Chem Biol 13:387–397. doi:10.1016/j.chembiol.2006.02.002

    Article  CAS  Google Scholar 

  • Bate N, Butler AR, Gandecha AR, Cundliffe E (1999) Multiple regulatory genes in the tylosin biosynthetic c luster of Streptomyces fradiae. Chem Biol 6:617–624. doi:10.1016/S1074-5521(99)80113-6

    Article  CAS  Google Scholar 

  • Bate N, Bignell DRD, Cundliffe E (2006) Regulation of tylosin biosynthesis involving ‘SARP-helper’ activity. Mol Microbiol 62:148–156. doi:10.1111/j.1365-2958.2006.05338.x

    Article  CAS  Google Scholar 

  • Bhukya H, Bhujbalrao R, Bitra A, Anand R (2014) Structural and functional basis of transcriptional regulation by TetR family protein CprB from S. coelicolor A3(2). Nucleic Acids Res. doi:10.1093/nar/gku587

    Google Scholar 

  • Bibb M (1996) The regulation of antibiotic production in Streptomyces coelicolor A3(2). Microbiology 142:1335–1344

    Article  CAS  Google Scholar 

  • Bibb MJ (2005) Regulation of secondary metabolism in streptomycetes. Curr Opin Microbiol 8:208–215. doi:10.1016/j.mib.2005.02.016

    Article  CAS  Google Scholar 

  • Bignell DRD, Bate N, Cundliffe E (2007) Regulation of tylosin production: role of a TylP-interactive ligand. Mol Microbiol 63:838–847. doi:10.1111/j.1365-2958.2006.05541.x

    Article  CAS  Google Scholar 

  • Carmody M et al (2004) Analysis and manipulation of amphotericin biosynthetic genes by means of modified phage KC515 transduction techniques. Gene 343:107–115. doi:10.1016/j.gene.2004.08.006

    Article  CAS  Google Scholar 

  • Chang H, Chen MY, Shieh YT, Bibb MJ, Chen CW (1996) The cutRS signal transduction system of Streptomyces lividans represses the biosynthesis of the polyketide antibiotic actinorhodin. Mol Microbiol 21:1075–1085

    CAS  Google Scholar 

  • Chen S et al (2003) Organizational and mutational analysis of a complete FR-008/Candicidin gene cluster encoding a structurally related polyene complex. Chem Biol 10:1065–1076. doi:10.1016/j.chembiol.2003.10.007

    Article  CAS  Google Scholar 

  • Chen Y, Wendt-Pienkowski E, Shen B (2008) Identification and utility of FdmR1 as a Streptomyces antibiotic regulatory protein activator for fredericamycin production in Streptomyces griseus ATCC 49344 and heterologous hosts. J Bacteriol 190:5587–5596. doi:10.1128/jb.00592-08

    Article  CAS  Google Scholar 

  • Den Hengst CD, Tran NT, Bibb MJ, Chandra G, Leskiw BK, Buttner MJ (2010) Genes essential for morphological development and antibiotic production in Streptomyces coelicolor are targets of BldD during vegetative growth. Mol Microbiol 78:361–379. doi:10.1111/j.1365-2958.2010.07338.x

    Article  CAS  Google Scholar 

  • Distler J, Ebert A, Mansouri K, Pissowotzki K, Stockmann M, Piepersberg W (1987) Gene cluster for streptomycin biosynthesis in Streptomyces griseus: nucleotide sequence of three genes and analysis of transcriptional activity. Nucleic Acids Res 15:8041–8056

    Article  CAS  Google Scholar 

  • Dun J et al (2015) PapR6, a putative atypical response regulator. Functions as a pathway-specific activator of pristinamycin II biosynthesis in Streptomyces pristinaespiralis. J Bacteriol 197:441–450. doi:10.1128/jb.02312-14

    Article  CAS  Google Scholar 

  • Fernández-Moreno MA, Caballero J, Hopwood DA, Malpartida F (1991) The act cluster contains regulatory and antibiotic export genes, direct targets for translational control by the bldA tRNA gene of streptomyces. Cell 66:769–780. doi:10.1016/0092-8674(91)90120-N

    Article  Google Scholar 

  • Gallegos MT, Schleif R, Bairoch A, Hofmann K, Ramos JL (1997) Arac/XylS family of transcriptional regulators. Microbiol Mol Biol Rev 61:393–410

    CAS  Google Scholar 

  • Gao C, Hindra, Mulder D, Yin C, Elliot MA (2012) Crp is a global regulator of antibiotic production in Streptomyces. MBio 3:1–12. doi:10.1128/mBio.00407-12

    Article  CAS  Google Scholar 

  • Garg RP, Parry RJ (2010) Regulation of valanimycin biosynthesis in Streptomyces viridifaciens: characterization of VlmI as a Streptomyces antibiotic regulatory protein (SARP). Microbiology 156:472–483. doi:10.1099/mic.0.033167-0

    Article  CAS  Google Scholar 

  • Ghorbel S, Smirnov A, Chouayekh H, Sperandio B, Esnault C, Kormanec J, Virolle M-J (2006) Regulation of ppk expression and in vivo function of Ppk in Streptomyces lividans TK24. J Bacteriol 188:6269–6276. doi:10.1128/jb.00202-06

    Article  CAS  Google Scholar 

  • Guthrie EP, Flaxman CS, White J, Hodgson DA, Bibb MJ, Chater KF (1998) A response-regulator-like activator of antibiotic synthesis from Streptomyces coelicolor A3(2) with an amino-terminal domain that lacks a phosphorylation pocket. Microbiology 144 (3):727–738. doi:10.1099/00221287-144-3-727

    Article  CAS  Google Scholar 

  • Hakenbeck R, Stock JB (1996) Analysis of two-component signal transduction systems involved in transcriptional regulation. Methods Enzymol 273:281–300. doi:10.1016/S0076-6879(96)73026-4

    Article  CAS  Google Scholar 

  • He W, Lei J, Liu Y, Wang Y (2008) Regulatory genes of geldanamycin biosynthesis. Chin J Biotechnol 24:717–722

    Article  CAS  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 19:259–274. doi:10.1093/dnares/dss010

    Article  CAS  Google Scholar 

  • Hong B, Phornphisutthimas S, Tilley E, Baumberg S, McDowall KJ (2007) Streptomycin production by Streptomyces griseus can be modulated by a mechanism not associated with change in the adpA component of the A-factor cascade. Biotechnol Lett 29:57–64. doi:10.1007/s10529-006-9216-2

    Article  CAS  Google Scholar 

  • Horinouchi S, Malpartida F, Hopwood D, Beppu T (1989) afsB stimulates transcription of the actinorhodin biosynthetic pathway in Streptomyces coelicolor A3(2) and Streptomyces lividans. Mol Gen Genet 215:355–357. doi:10.1007/bf00339742

    Article  CAS  Google Scholar 

  • Hsiao N-H et al (2009) Analysis of two additional signaling molecules in Streptomyces coelicolor and the development of a butyrolactone-specific reporter system. Chem Biol 16:951–960. doi:10.1016/j.chembiol.2009.08.010

    Article  CAS  Google Scholar 

  • Huang J, Lih CJ, Pan KH, Cohen SN (2001) Global analysis of growth phase responsive gene expression and regulation of antibiotic biosynthetic pathways in Streptomyces coelicolor using DNA microarrays. Genes Dev 15:3183–3192. doi:10.1101/gad.943401

    Article  CAS  Google Scholar 

  • Huang J et al (2005) Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor. Mol Microbiol 58:1276–1287. doi:10.1111/j.1365-2958.2005.04879.x

    Article  CAS  Google Scholar 

  • Huang M, Li M, Feng Z, Liu Y, Chu Y, Tian Y (2011) Enhanced rapamycin production in Streptomyces hygroscopicus by integrative expression of aveR, a LAL family transcriptional regulator. World J Microbiol Biotechnol 27:2103–2109. doi:10.1007/s11274-011-0673-y

    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. doi:10.1099/mic.0.27181-0

    Article  CAS  Google Scholar 

  • Hwang YS, Kim ES, Biró S, Choi CY (2003) Cloning and analysis of a DNA fragment stimulating avermectin production in various Streptomyces avermitilis strains. Appl Environ Microbiol 69:1263–1269. doi:10.1128/aem.69.2.1263-1269.2003

    Article  CAS  Google Scholar 

  • Ikeda H et al. (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotech 21:526–531. http://www.nature.com/nbt/journal/v21/n5/suppinfo/nbt820_S1.html

  • Ishizuka H, Horinouchi S, Kieser HM, Hopwood DA, Beppu T (1992) A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J Bacteriol 174:7585–7594

    Article  CAS  Google Scholar 

  • Kang S-H, Huang J, Lee HN, Hur YA, Cohen SN, Kim KS (2007) Interspecies DNA microarray analysis identifies WblA as a pleiotropic down-regulator of antibiotic biosynthesis in Streptomyces. J Bacteriol 189:4315–4319. doi:10.1128/jb.01789-06

    Article  CAS  Google Scholar 

  • Kato J-Y, 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. doi:10.1128/jb.186.7.2206-2211.2004

    Article  CAS  Google Scholar 

  • Kitani S, Yamada Y, Nihira T (2001) Gene replacement analysis of the butyrolactone autoregulator receptor (FarA) reveals that FarA acts as a novel regulator in secondary metabolism of Streptomyces lavendulae FRI-5. J Bacteriol 183:4357–4363. doi:10.1128/jb.183.14.4357-4363.2001

    Article  CAS  Google Scholar 

  • Kitani S, Iida A, Izumi T, Maeda A, Yamada Y, Nihira T (2008) Identification of genes involved in the butyrolactone autoregulator cascade that modulates secondary metabolism in Streptomyces lavendulae FRI-5. Gene 425:9–16. doi:10.1016/j.gene.2008.07.043

    Article  CAS  Google Scholar 

  • Kurniawan Y, Kitani S, Maeda A, Nihira T (2014) Differential contributions of two SARP family regulatory genes to indigoidine biosynthesis in Streptomyces lavendulae FRI-5. Appl Microbiol Biotechnol 98:9713–9721. doi:10.1007/s00253-014-5988-9

    Article  CAS  Google Scholar 

  • Kuščer E, Coates N, Challis I, Gregory M, Wilkinson B, Sheridan R, Petković H (2007) Roles of rapH and rapG in positive regulation of rapamycin biosynthesis in Streptomyces hygroscopicus. J Bacteriol 189:4756–4763. doi:10.1128/jb.00129-07

    Article  CAS  Google Scholar 

  • Lee JY, Hwang YS, Kim SS, Kim ES, Choi CY (2000) Effect of a global regulatory gene, afsR2, from Streptomyces lividans on avermectin production in Streptomyces avermitilis. J Biosci Bioeng 89:606–608. doi:10.1016/S1389-1723(00)80065-1

    Article  CAS  Google Scholar 

  • Lei J, He W, Wang Y (2007) Regulatory mechanism of morphological differentiation and secondary metabolism in Streptomyces. Pharm Biotechnol 14:225–229

    Google Scholar 

  • Li R et al (2009) polR, a pathway-specific transcriptional regulatory gene, positively controls polyoxin biosynthesis in Streptomyces cacaoi subsp. asoensis. Microbiology 155:1819–1831. doi:10.1099/mic.0.028639-0

    Article  CAS  Google Scholar 

  • Li Q, Wang L, Xie Y, Wang S, Chen R, Hong B (2013) SsaA, a member of a novel class of transcriptional regulators, controls sansanmycin production in Streptomyces sp. Strain SS through a feedback mechanism. J Bacteriol 195:2232–2243. doi:10.1128/jb.00054-13

    Article  CAS  Google Scholar 

  • Li X, Wang J, Li SS, Ji JJ, Wang WS, Yang KQ (2015a) ScbR- and ScbR2-mediated signal transduction networks coordinate complex physiological responses in Streptomyces coelicolor. Sci Rep 5:14831. doi:10.1038/srep14831

    Article  CAS  Google Scholar 

  • Li X et al (2015b) Binding of a biosynthetic intermediate to AtrA modulates the production of lidamycin by Streptomyces globisporus. Mol Microbiol 96:1257–1271. doi:10.1111/mmi.13004

    Article  CAS  Google Scholar 

  • Liu J, Yang K (2006) Functional analyses of TcrA-a TPR-containing regulatory protein in Streptomyces coelicolor A3(2). Wei Sheng Wu Xve Bao 46:33–37

    CAS  Google Scholar 

  • Lu Y, Jiang W (2013) Perspectives on two-component systems involved in regulation of secondary metabolism in Streptomyces. Microbiol China 40:1847–1859

    CAS  Google Scholar 

  • Lu Y et al (2007) Characterization of a novel two-component regulatory system involved in the regulation of both actinorhodin and a type I polyketide in Streptomyces coelicolor. Appl microbiol biotechnol 77:625–635. doi:10.1007/s00253-007-1184-5

    Article  CAS  Google Scholar 

  • Lu Y et al (2011) An orphan histidine kinase, OhkA, regulates both secondary metabolism and morphological differentiation in Streptomyces coelicolor. J Bacteriol 193:3020–3032. doi:10.1128/jb.00017-11

    Article  CAS  Google Scholar 

  • Madduri K, Hutchinson CR (1995) Functional characterization and transcriptional analysis of the dnrR1 locus, which controls daunorubicin biosynthesis in Streptomyces peucetius. J Bacteriol 177:1208–1215. doi:10.1128/jb.177.5.1208-1215.1995

    Article  CAS  Google Scholar 

  • Malla S, Niraula NP, Liou K, Sohng JK (2010) Improvement in doxorubicin productivity by overexpression of regulatory genes in Streptomyces peucetius. Res Microbiol 161:109–117. doi:10.1016/j.resmic.2009.12.003

    Article  CAS  Google Scholar 

  • Mao X, Sun Z, Liang B, Wang Z, Feng W, Huang F, Li Y (2013) Positive feedback regulation of stgR expression for secondary metabolism in Streptomyces coelicolor. J Bacteriol 195:2072–2078. doi:10.1128/jb.00040-13

    Article  CAS  Google Scholar 

  • Martín J-F, Liras P (2010) Engineering of regulatory cascades and networks controlling antibiotic biosynthesis in Streptomyces. Curr Opin Microbiol 13:263–273. doi:10.1016/j.mib.2010.02.008

    Article  CAS  Google Scholar 

  • Mast Y, Guezguez J, Handel F, Schinko E (2015) A complex signaling cascade governs pristinamycin biosynthesis in Streptomyces pristinaespiralis. Appl Env Microbiol 81:6621–6636. doi:10.1128/aem.00728-15

    Article  CAS  Google Scholar 

  • Matsuno K, Yamada Y, Lee CK, Nihira T (2003) Identification by gene deletion analysis of barB as a negative regulator controlling an early process of virginiamycin biosynthesis in Streptomyces virginiae. Arch Microbiol 181:52–59. doi:10.1007/s00203-003-0625-5

    Article  CAS  Google Scholar 

  • Miyamoto KT, Kitani S, Komatsu M, Ikeda H, Nihira T (2011) The autoregulator receptor homologue AvaR3 plays a regulatory role in antibiotic production, mycelial aggregation and colony development of Streptomyces avermitilis. Microbiology 157:2266–2275. doi:10.1099/mic.0.048371-0

    Article  CAS  Google Scholar 

  • Nakano H, Lee C-K, Nihira T, Yamada Y (2000) A null mutant of the Streptomyces virginiae barA gene encoding a butyrolactone autoregulator receptor and its phenotypic and transcriptional analysis. J Biosci Bioeng 90:204–207. doi:10.1016/S1389-1723(00)80111-5

    Article  CAS  Google Scholar 

  • Namwat W, Lee CK, Kinoshita H, Yamada Y, Nihira T (2001) Identification of the varR gene as a transcriptional regulator of virginiamycin S resistance in Streptomyces virginiae. J Bacteriol 183:2025–2031. doi:10.1128/jb.183.6.2025-2031.2001

    Article  CAS  Google Scholar 

  • Novakova R, Homerova D, Feckova L, Kormanec J (2005) Characterization of a regulatory gene essential for the production of the angucycline-like polyketide antibiotic auricin in Streptomyces aureofaciens CCM 3239. Microbiology 151:2693–2706. doi:10.1099/mic.0.28019-0

    Article  CAS  Google Scholar 

  • Novakova R, Kutas P, Feckova L, Kormanec J (2010) The role of the TetR-family transcriptional regulator Aur1R in negative regulation of the auricin gene cluster in Streptomyces aureofaciens CCM 3239. Microbiology 156:2374–2383. doi:10.1099/mic.0.037895-0

    Article  CAS  Google Scholar 

  • Novakova R, Rehakova A, Kutas P, Feckova L, Kormanec J (2011) The role of two SARP family transcriptional regulators in regulation of the auricin gene cluster in Streptomyces aureofaciens CCM 3239. Microbiology 157:1629–1639. doi:10.1099/mic.0.047795-0

    Article  CAS  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. doi:10.1046/j.1365-2958.1999.01579.x

    Article  CAS  Google Scholar 

  • Ohnishi Y, Yamazaki H, Kato J, 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. doi:10.1271/bbb.69.431

    Article  CAS  Google Scholar 

  • Oliynyk M et al (2003) Analysis of the biosynthetic gene cluster for the polyether antibiotic monensin in Streptomyces cinnamonensis and evidence for the role of monB and monC genes in oxidative cyclization. Mol Microbiol 49:1179–1190. doi:10.1046/j.1365-2958.2003.03571.x

    Article  CAS  Google Scholar 

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

    Article  CAS  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. doi:10.1046/j.1365-2958.1998.00832.x

    Article  CAS  Google Scholar 

  • Ostash B et al (2011) Identification and characterization of the Streptomyces globisporus 1912 regulatory gene lndYR that affects sporulation and antibiotic production. Microbiology 157:1240–1249. doi:10.1099/mic.0.045088-0

    Article  CAS  Google Scholar 

  • Otten SL, Ferguson J, Hutchinson CR (1995) Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus. J Bacteriol 177:1216–1224

    Article  CAS  Google Scholar 

  • Otten SL, Olano C, Hutchinson CR (2000) The dnrO gene encodes a DNA-binding protein that regulates daunorubicin production in Streptomyces peucetius by controlling expression of the dnrN pseudo response regulator gene. Microbiology 146:1457–1468. doi:10.1099/00221287-146-6-1457

    Article  CAS  Google Scholar 

  • Ou X, Zhang B, Zhang L, Zhao G, Ding X (2009) Characterization of rrdA, a TetR family protein gene involved in the regulation of secondary metabolism in Streptomyces coelicolor. Appl Environ Microbiol 75:2158–2165. doi:10.1128/aem.02209-08

    Article  CAS  Google Scholar 

  • Palaniappan N, Ayers S, Gupta S, Habib ES, Reynolds KA (2006) Production of hygromycin A Analogs in Streptomyces hygroscopicus NRRL 2388 through identification and manipulation of the biosynthetic gene cluster. Chem Biol 13:753–764. doi:10.1016/j.chembiol.2006.05.013

    Article  CAS  Google Scholar 

  • Parajuli N, Moon YH (2002) Analysis of doxorubicin biosynthetic gene cluster and intensive study of regulatory system of Streptomyces peucetious ATCC 27952. Theor Appl Chem Eng 8:3909–3912

    Google Scholar 

  • Parajuli N, Viet HT, Ishida K, Tong HT, Lee HC, Liou K, Sohng JK (2005) Identification and characterization of the afsR homologue regulatory gene from Streptomyces peucetius ATCC 27952. Res Microbiol 156:707–712. doi:10.1016/j.resmic.2005.03.005

    Article  CAS  Google Scholar 

  • Pérez-Llarena FJ, Liras P, Rodríguez-García A, Martín JF (1997) A regulatory gene (ccaR) required for cephamycin and clavulanic acid production in Streptomyces clavuligerus: amplification results in overproduction of both beta-lactam compounds. J Bacteriol 179:2053–2059

    Article  Google Scholar 

  • Pérez-Redondo R, Rodríguez-García A, Martín JF, Liras P (1998) The claR gene of Streptomyces clavuligerus, encoding a LysR-type regulatory protein controlling clavulanic acid biosynthesis, is linked to the clavulanate-9-aldehyde reductase (car) gene. Gene 211:311–321. doi:10.1016/S0378-1119(98)00106-1

    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 Genom 12:1–14. doi:10.1186/1471-2164-12-175

    Article  CAS  Google Scholar 

  • Pulsawat N, Kitani S, Nihira T (2007) Characterization of biosynthetic gene cluster for the production of virginiamycin M, a streptogramin type A antibiotic, in Streptomyces virginiae. Gene 393:31–42. doi:10.1016/j.gene.2006.12.035

    Article  CAS  Google Scholar 

  • Pulsawat N, Kitani S, Fukushima E, Nihira T (2009) Hierarchical control of virginiamycin production in Streptomyces virginiae by three pathway-specific regulators: VmsS, VmsT and VmsR. Microbiology 155:1250–1259. doi:10.1099/mic.0.022467-0

    Article  CAS  Google Scholar 

  • Räty K, Kantola J, Hautala A, Hakala J, Ylihonko K, Mäntsälä P (2002) Cloning and characterization of Streptomyces galilaeus aclacinomycins polyketide synthase (PKS) cluster. Gene 293:115–122. doi:10.1016/S0378-1119(02)00699-6

    Article  Google Scholar 

  • Rehakova A, Novakova R, Feckova L, Mingyar E, Kormanec J (2013) A gene determining a new member of the SARP family contributes to transcription of genes for the synthesis of the angucycline polyketide auricin in Streptomyces aureofaciens CCM 3239. FEMS Microbiol Lett 346:45–55

    Article  CAS  Google Scholar 

  • Retzlaff L, Distler J (1995) The regulator of streptomycin gene expression, StrR, of Streptomyces griseus is a DNA binding activator protein with multiple recognition sites. Mol Microbiol 18:151–162. doi:10.1111/j.1365-2958.1995.mmi_18010151.x

    Article  CAS  Google Scholar 

  • Rodríguez M, Núñez LE, Braña AF, Méndez C, Salas JA, Blanco G (2008) Identification of transcriptional activators for thienamycin and cephamycin C biosynthetic genes within the thienamycin gene cluster from Streptomyces cattleya. Mol Microbiol 69:633–645. doi:10.1111/j.1365-2958.2008.06312.x

    Article  CAS  Google Scholar 

  • Rodríguez H, Rico S, Díaz M, Santamaría RI (2013) Two-component systems in Streptomyces: key regulators of antibiotic complex pathways. Microb Cell Fact 12:127. doi:10.1186/1475-2859-12-127

    Article  CAS  Google Scholar 

  • Romero-Rodríguez A, Robledo-Casados I, Sánchez S (2015) An overview on transcriptional regulators in Streptomyces. Biochem Biophys Acta 1849:1017–1039. doi:10.1016/j.bbagrm.2015.06.007

    Google Scholar 

  • Sato K, Nihira T, Sakuda S, Yanagimoto M, Yamada Y (1989) Isolation and structure of a new butyrolactone autoregulator from Streptomyces sp. FRI-5. J Ferment Bioeng 68:170–173. doi:10.1016/0922-338X(89)90131-1

    Article  CAS  Google Scholar 

  • Sekurova ON et al (2004) In vivo analysis of the regulatory genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455 reveals their differential control over antibiotic biosynthesis. J Bacteriol 186:1345–1354. doi:10.1128/jb.186.5.1345-1354.2004

    Article  CAS  Google Scholar 

  • Sheeler NL, MacMillan SV, Nodwell JR (2005) Biochemical activities of the absA two-component system of Streptomyces coelicolor. J Bacteriol 187:687–696. doi:10.1128/jb.187.2.687-696.2005

    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 A100:6133–6138. doi:10.1073/pnas.0931429100

    Article  CAS  Google Scholar 

  • Stock AM, Robinson VL, Goudreau PN (2000) Two-component signal transduction. Annu Rev Biochem 69:183–215. doi:10.1146/annurev.biochem.69.1.183

    Article  CAS  Google Scholar 

  • Stratigopoulos G, Cundliffe E (2002) Expression analysis of the tylosin-biosynthetic gene cluster: pivotal regulatory role of the tylQ product. Chem Biol 9:71–78. doi:10.1016/S1074-5521(01)00095-3

    Article  CAS  Google Scholar 

  • Suzuki T, Mochizuki S, Yamamoto S, Arakawa K, Kinashi H (2010) Regulation of lankamycin biosynthesis in Streptomyces rochei by two SARP genes, srrY and srrZ. Biosci Biotechnol Biochem 74:819–827. doi:10.1271/bbb.90927

    Article  CAS  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. doi:10.1111/j.1365-2958.1992.tb01459.x

    Article  CAS  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. doi:10.1111/j.1365-2958.2005.04543.x

    Article  CAS  Google Scholar 

  • Tanaka A, Takano Y, Ohnishi Y, Horinouchi S (2007) AfsR recruits RNA polymerase to the afsS promoter: a model for transcriptional activation by SARPs. J Mol Biol 369:322–333. doi:10.1016/j.jmb.2007.02.096

    Article  CAS  Google Scholar 

  • Wang L et al (2009a) Autoregulation of antibiotic biosynthesis by binding of the end product to an atypical response regulator. Proc Natl Acad Sci USA 106:8617–8622. doi:10.1073/pnas.0900592106

    Article  CAS  Google Scholar 

  • Wang W, Shu D, Chen L, Jiang W, Lu Y (2009b) Cross-talk between an orphan response regulator and a noncognate histidine kinase in Streptomyces coelicolor. FEMS Microbiol Lett 294:150–156. doi:10.1111/j.1574-6968.2009.01563.x

    Article  CAS  Google Scholar 

  • Wilson DJ, Xue Y, Reynolds KA, Sherman DH (2001) Characterization and analysis of the PikD regulatory factor in the pikromycin biosynthetic pathway of Streptomyces venezuelae. J Bacteriol 183:3468–3475. doi:10.1128/jb.183.11.3468-3475.2001

    Article  CAS  Google Scholar 

  • Xie PF, Sheng Y, Ito T, Mahmud T (2012) Transcriptional regulation and increased production of asukamycin in engineered Streptomyces nodosus subsp. asukaensis strains. Appl Microbiol Biotechnol 96:451–460. doi:10.1007/s00253-012-4084-2

    Article  CAS  Google Scholar 

  • Xue Y, Zhao L, Liu HW, Sherman DH (1998) A gene cluster for macrolide antibiotic biosynthesis in Streptomyces venezuelae: architecture of metabolic diversity. Proc Natl Acad Sci USA 95:12111–12116. doi:10.1073/pnas.95.21.12111

    Article  CAS  Google Scholar 

  • Yamada Y, Sugamura K, Kondo K, Yanagimoto M, Okada H (1987) The structure of inducing factors for virginiamycin production in Streptomyces virginiae. J Antibiot 40:496–504. doi:10.7164/antibiotics.40.496

    Article  CAS  Google Scholar 

  • Yang K, Han L, He J, Wang L, Vining LC (2001) A repressor-response regulator gene pair controlling jadomycin B production in Streptomyces venezuelae ISP5230. Gene 279:165–173. doi:10.1016/S0378-1119(01)00723-5

    Article  CAS  Google Scholar 

  • Yepes A, Rico S, Rodríguez-García A, Santamaría RI, Díaz M (2011) Novel two-component systems implied in antibiotic production in Streptomyces coelicolor. PLoS ONE 6:e19980. doi:10.1371/journal.pone.0019980

    Article  CAS  Google Scholar 

  • Yoo YJ, Hwang JY, Shin HL (2015) Characterization of negative regulatory genes for the biosynthesis of rapamycin in Streptomyces rapamycinicus and its application for improved production. Microbiol Biotechnol 42:125–135

    Article  CAS  Google Scholar 

  • Yu Z, Wang Q, Deng Z, Tao M (2006) Activation of silent antibiotic synthesis in Streptomyces lividans by disruption of a negative regulator nsdA, a gene conserved in Streptomyces Chinese. J Biotechnol 22:757–762

    CAS  Google Scholar 

  • Yu Q, Du A, Liu T, Deng Z, He X (2012) The biosynthesis of the polyether antibiotic nanchangmycin is controlled by two pathway-specific transcriptional activators. Arch Microbiol 194:415–426. doi:10.1007/s00203-011-0768-8

    Article  CAS  Google Scholar 

  • Zhang Y, Zou Z, Niu G, Tan H (2013) jadR* and jadR2 act synergistically to repress jadomycin biosynthesis. Sci China Life Sci 56:584–590. doi:10.1007/s11427-013-4508-y

    Article  CAS  Google Scholar 

  • Zhu D, He X, Zhou X, Deng Z (2005) Expression of the melC operon in several streptomyces strains is positively regulated by AdpA, an AraC family transcriptional regulator involved in morphological development in Streptomyces coelicolor. J Bacteriol 187:3180–3187. doi:10.1128/jb.187.9.3180-3187.2005

    Article  CAS  Google Scholar 

  • Zou Z, Du D, Zhang Y, Zhang J, Niu G, Tan H (2014) A γ-butyrolactone-sensing activator/repressor, JadR3, controls a regulatory mini-network for jadomycin biosynthesis. Mol Microbiol 94:490–505. doi:10.1111/mmi.12752

    Article  CAS  Google Scholar 

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Acknowledgements

This work is supported by the Open Research Program of Key Laboratory of Synthetic Biology, the Chinese Academy of Sciences (SYN201612) and the Key Program of Sichuan Science and Technology Project (2017GZ0430). The authors thank all the supporting institutions.

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Correspondence to Yongqiang Tian.

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This study was funded by the Open Research Program of Key Laboratory of Synthetic Biology, the Chinese Academy of Sciences (SYN201612) and the Key Program of Sichuan Science and Technology Project (2017GZ0430).

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Lu, F., Hou, Y., Zhang, H. et al. Regulatory genes and their roles for improvement of antibiotic biosynthesis in Streptomyces . 3 Biotech 7, 250 (2017). https://doi.org/10.1007/s13205-017-0875-6

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