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Biosynthesis of phloroglucinol compounds in microorganisms—review

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Abstract

Phloroglucinol derivatives are a major class of secondary metabolites of wide occurrence in biological systems. In the bacteria kingdom, these compounds can only be synthesized by some species of Pseudomonads. Pseudomonas spp. could produce 2,4-diacetylphloroglucinol (DAPG) that plays an important role in the biological control of many plant pathogens. In this review, we summarize knowledge about synthesis of phloroglucinol compounds based on the DAPG biosynthetic pathway. Recent advances that have been made in understanding phloroglucinol compound biosynthesis and regulation are highlighted. From these studies, researchers have identified the biosynthesis pathway of DAPG. Most of the genes involved in the biosynthesis pathway have been cloned and characterized. Additionally, heterologous systems of the model microorganism Escherichia coli are constructed to produce phloroglucinol. Although further work is still required, a full understanding of phloroglucinol compound biosynthesis is almost within reach. This review also suggests new directions and attempts to gain some insights for better understanding of the biosynthesis and regulation of DAPG. The combination of traditional biochemistry and molecular biology with new systems biology and synthetic biology tools will provide a better view of phloroglucinol compound biosynthesis and a greater potential of microbial production.

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References

  • Abbas A, McGuire JE, Crowley D, Baysse C, Dow M, O’Gara F (2004) The putative permease PhlE of Pseudomonas fluorescens F113 has a role in 2,4-diacetylphloroglucinol resistance and in general stress tolerance. Microbiology 150(7):2443–2450

    Article  CAS  Google Scholar 

  • Abbas A, Morrissey JP, Marquez PC, Sheehan MM, Delany IR, O’Gara F (2002) Characterization of interactions between the transcriptional repressor PhlF and its binding site at the phlA promoter in Pseudomonas fluorescens F113. J Bacteriol 184(11):3008–3016

    Article  CAS  Google Scholar 

  • Abe I, Morita H (2010) Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases. Nat Prod Rep 27(6):809–838

    Article  CAS  Google Scholar 

  • Achkar J, Xian M, Zhao H, Frost JW (2005) Biosynthesis of phloroglucinol. J Am Chem Soc 127(15):5332–5333

    Article  CAS  Google Scholar 

  • Austin MB, Noel AJP (2003) The chalcone synthase superfamily of type III polyketide synthases. Nat Prod Rep 20(1):79–110

    Article  CAS  Google Scholar 

  • Bangera MG, Thomashow LS (1996) Characterization of a genomic locus required for synthesis of the antibiotic 2,4-diacetylphloroglucinol by the biological control agent Pseudomonas fluorescens Q2-87. Mol Plant-Microbe Interact 9(2):83–90

    Article  CAS  Google Scholar 

  • Bangera MG, Thomashow LS (1999) Identification and characterization of a gene cluster for synthesis of the polyketide antibiotic 2,4-diacetylphloroglucinol from Pseudomonas fluorescens Q2-87. J Bacteriol 181(10):3155–3163

    CAS  Google Scholar 

  • Bossis E, Lemanceau P, Latour X, Gardan L (2000) The taxonomy of Pseudomonas fluorescens and Pseudomonas putida: current status and need for revision. Agronomie 20(1):51–63

    Article  Google Scholar 

  • Bottiglieri M, Keel C (2006) Characterization of PhlG, a hydrolase that specifically degrades the antifungal compound 2,4-diacetylphloroglucinol in the biocontrol agent Pseudomonas fluorescens CHA0. Appl Environ Microbiol 72(1):418–427

    Article  CAS  Google Scholar 

  • Bult CJ, White O, Olsen GJ, Zhou LX, Fleischmann RD, Sutton GG, Blake JA, FitzGerald LM, Clayton RA, Gocayne JD, Kerlavage AR, Dougherty BA, Tomb JF, Adams MD, Reich CI, Overbeek R, Kirkness EF, Weinstock KG, Merrick JM, Glodek A, Scott JL, Geoghagen NSM, Weidman JF, Fuhrmann JL, Nguyen D, Utterback TR, Kelley JM, Peterson JD, Sadow PW, Hanna MC, Cotton MD, Roberts KM, Hurst MA, Kaine BP, Borodovsky M, Klenk HP, Fraser CM, Smith HO, Woese CR, Venter JC (1996) Complete genome sequence of the methanogenic archaeon, Methanococcus jannaschii. Science 273(5278):1058–1073

    Article  CAS  Google Scholar 

  • Cao Y, Jiang X, Zhang R, Xian M (2011) Improved phloroglucinol production by metabolically engineered Escherichia coli. Appl Microbiol Biotechnol 91(6):1545–1552

    Article  CAS  Google Scholar 

  • Cao Y, Xian M (2011) Production of phloroglucinol by Escherichia coli using a stationary-phase promoter. Biotechnol Lett 33(9):1853–1858

    Article  CAS  Google Scholar 

  • Cui H, C-g X, C-z L (2003) A novel chemiluminescent method for determination of phloroglucinol. Luminescence 18(6):318–323

    Article  CAS  Google Scholar 

  • De La Fuente L, Landa BB, Weller DM (2006a) Host crop affects rhizosphere colonization and competitiveness of 2,4-diacetylphloroglucinol-producing Pseudomonas fluorescens. Phytopathology 96(7):751–762

    Article  Google Scholar 

  • De La Fuente L, Mavrodi DV, Landa BB, Thomashow LS, Weller DM (2006b) phlD-based genetic diversity and detection of genotypes of 2,4-diacetylphloroglucinol-producing Pseudomonas fluorescens. FEMS Microbiol Ecol 56(1):64–78

    Article  Google Scholar 

  • Delany I, Sheehan MM, Fenton A, Bardin S, Aarons S, O’Gara F (2000) Regulation of production of the antifungal metabolite 2,4-diacetylphloroglucinol in Pseudomonas fluorescens F113: genetic analysis of phlF as a transcriptional repressor. Microbiology 146(2):537–546

    CAS  Google Scholar 

  • Delany IR, Walsh UF, Ross I, Fenton AM, Corkery DM, O’Gara F (2001) Enhancing the biocontrol efficacy of Pseudomonas fluorescens F113 by altering the regulation and production of 2,4-diacetylphloroglucinol—improved Pseudomonas biocontrol inoculants. Plant Soil 232(1–2):195–205

    Article  CAS  Google Scholar 

  • Dwivedi D, Johri BN (2003) Antifungals from fluorescent pseudomonads: biosynthesis and regulation. Curr Sci India 85(12):1693–1703

    CAS  Google Scholar 

  • Fenton AM, Stephens PM, Crowley J, O’Callaghan M, O’Gara F (1992) Exploitation of gene(s) involved in 2,4-diacetylphloroglucinol biosynthesis to confer a new biocontrol capability to a Pseudomonas strain. Appl Environ Microbiol 58(12):3873–3878

    CAS  Google Scholar 

  • Frost JW (2007) Biosynthesis of phloroglucinol and preparation of 1,3-dihydroxybenzene therefrom. Patent application no. 20070178571

  • Funa N, Ohnishi Y, Fujii I, Shibuya M, Ebizuka Y, Horinouchi S (1999) A new pathway for polyketide synthesis in microorganisms. Nature 400(6747):897–899

    Article  CAS  Google Scholar 

  • Gao H, Xiao D, Yang Y, Gao F, Pang S (2009) Cloning, expression and functioning of phlD genes from Pseudomonas fluorescens. Trans Beijing Inst Technol 29(5):465–470

    CAS  Google Scholar 

  • Gao X, Wang P, Tang Y (2010) Engineered polyketide biosynthesis and biocatalysis in Escherichia coli. Appl Microbiol Biotechnol 88(6):1233–1242

    Article  CAS  Google Scholar 

  • Haas D, Keel C (2003) Regulation of antibiotic production in root-colonizing Peudomonas spp. and relevance for biological control of plant disease. Annu Rev Phytopathol 41(1):117–153

    Article  CAS  Google Scholar 

  • He Y-X, Huang L, Xue Y, Fei X, Teng Y-B, Rubin-Pitel SB, Zhao H, Zhou C-Z (2010) Crystal structure and computational analyses provide insights into the catalytic mechanism of 2,4-diacetylphloroglucinol hydrolase PhlG from Pseudomonas fluorescens. J Biol Chem 285(7):4603–4611

    Article  CAS  Google Scholar 

  • Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A (2007) Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat Prod Rep 24(1):162–190

    Article  CAS  Google Scholar 

  • Ismaili L, Refouvelet B, Xicluna A, Robert JF, Guillaume YC (2003) Phloroglucinol: novel synthesis and role of the magnesium cation on its binding with human serum albumin (HSA) using a biochromatographic approach based on Langmuir isotherms. J Pharm Biomed Anal 32(3):549–553

    Article  CAS  Google Scholar 

  • Isnansetyo A, Kamei Y (2009) Bioactive substances produced by marine isolates of Pseudomonas. J Ind Microbiol Biotechnol 36(10):1239–1248

    Article  CAS  Google Scholar 

  • Kastens ML, Kaplan JF (1950) TNT into phloroglucinol. Ind Eng Chem 42(3):402–413

    Article  CAS  Google Scholar 

  • Lee SY, Park JM, Kim TY (2009) Constraints-based genome-scale metabolic simulation for systems metabolic engineering. Biotechnol Adv 27(6):979–988

    Article  Google Scholar 

  • Li TL, Choroba OW, Hong H, Williams DH, Spencer JB (2001) Biosynthesis of the vancomycin group of antibiotics: characterisation of a type III polyketide synthase in the pathway to (S)-3,5-dihydroxyphenylglycine. Chem Commun 20:2156–2157

    Article  Google Scholar 

  • Li YY, Muller R (2009) Non-modular polyketide synthases in myxobacteria. Phytochemistry 70(15–16):1850–1857

    Article  CAS  Google Scholar 

  • Loper J, Gross H (2007) Genomic analysis of antifungal metabolite production by Pseudomonas fluorescens Pf-5. Eur J Plant Pathol 119(3):265–278

    Article  CAS  Google Scholar 

  • Ma D, Alberti M, Lynch C, Nikaido H, Hearst JE (1996) The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol Microbiol 19(1):101–112

    Article  CAS  Google Scholar 

  • Matano I, Tsunekawa M, Shimizu S, Tanaka I, Mitsukura K, Maruyama K (2010) The chloride ion is an environmental factor affecting the biosynthesis of pyoluteorin and 2,4-diacetylphloroglucinol in Pseudomonas sp. YGJ3. Biosci Biotechnol Biochem 74(2):427–429

    Article  CAS  Google Scholar 

  • McKillop A, Howarth BD, Kobylecki RJ (1974) A simple and inexpensive procedure for the preparation of phloroglucinol and phloroglucinol trimethyl ether. Synth Commun 4(1):35–43

    Article  CAS  Google Scholar 

  • Moynihan JA, Morrissey JP, Coppoolse ER, Stiekema WJ, O’Gara F, Boyd EF (2009) Evolutionary history of the phl gene cluster in the plant-associated bacterium Pseudomonas fluorescens. Appl Environ Microbiol 75(7):2122–2131

    Article  CAS  Google Scholar 

  • Nakata K, Yoshimoto A, Yamada Y (1999) Promotion of antibiotic production by high ethanol, high NaCl concentration, or heat shock in Pseudomonas fluorescens S272. Biosci Biotechnol Biochem 63(2):293–297

    Article  CAS  Google Scholar 

  • Notz R, Maurhofer M, Dubach H, Haas D, Defago G (2002) Fusaric acid-producing strains of Fusarium oxysporum alter 2,4-diacetylphloroglucinol biosynthetic gene expression in Pseudomonas fluorescens CHA0 in vitro and in the rhizosphere of wheat. Appl Environ Microbiol 68(5):2229–2235

    Article  CAS  Google Scholar 

  • Notz R, Maurhofer M, Schnider-Keel U, Duffy B, Haas D, Défago G (2001) Biotic factors affecting expression of the 2,4-diacetylphloroglucinol biosynthesis gene phlA in Pseudomonas fluorescens biocontrol strain CHA0 in the rhizosphere. Phytopathology 91(9):873–881

    Article  CAS  Google Scholar 

  • Paulin MM, Novinscak A, St-Arnaud M, Goyer C, DeCoste NJ, Privé J-P, Owen J, Filion M (2009) Transcriptional activity of antifungal metabolite-encoding genes phlD and hcnBC in Pseudomonas spp. using qRT-PCR. FEMS Microbiol Ecol 68(2):212–222

    Article  CAS  Google Scholar 

  • Paulsen IT, Press CM, Ravel J, Kobayashi DY, Myers GSA, Mavrodi DV, DeBoy RT, Seshadri R, Ren Q, Madupu R, Dodson RJ, Durkin AS, Brinkac LM, Daugherty SC, Sullivan SA, Rosovitz MJ, Gwinn ML, Zhou L, Schneider DJ, Cartinhour SW, Nelson WC, Weidman J, Watkins K, Tran K, Khouri H, Pierson EA, Pierson LS, Thomashow LS, Loper JE (2005) Complete genome sequence of the plant commensal Pseudomonas fluorescens Pf-5. Nat Biotech 23(7):873–878

    Article  CAS  Google Scholar 

  • Picard C, Bosco M (2003) Genetic diversity of phlD gene from 2,4-diacetylphloroglucinol-producing Pseudomonas spp. strains from the maize rhizosphere. FEMS Microbiol Lett 219(2):167–172

    Article  CAS  Google Scholar 

  • Raaijmakers JM, Weller DM (1998) Natural plant protection by 2,4-diacetylphloroglucinol-producing Pseudomonas spp. in take-all decline soils. Mol Plant Microbe In 11(2):144–152

    Article  CAS  Google Scholar 

  • Rainer Z, Helmut M (1981) Process for the preparation of phloroglucinol. Patent application no. 4296260

  • Ramette A, Moënne-Loccoz Y, Défago G (2003) Prevalence of fluorescent pseudomonads producing antifungal phloroglucinols and/or hydrogen cyanide in soils naturally suppressive or conducive to tobacco black root rot. FEMS Microbiol Ecol 44(1):35–43

    Article  CAS  Google Scholar 

  • Ramette A, Moenne-Loccoz Y, Defago G (2001) Polymorphism of the polyketide synthase gene phlD in biocontrol fluorescent pseudomonads producing 2,4-diacetylphloroglucinol and comparison of PhlD with plant polyketide synthases. Mol Plant-Microbe Interact 14(5):639–652

    Article  CAS  Google Scholar 

  • Saharan K, Sarma MVRK, Prakash A, Johri BN, Bisaria VS, Sahai V (2011) Shelf-life enhancement of bio-inoculant formulation by optimizing the trace metals ions in the culture medium for production of DAPG using fluorescent pseudomonad R62. Enzyme Microb Technol 48(1):33–38

    Article  CAS  Google Scholar 

  • Sarniguet A, Kraus J, Henkels MD, Muehlchen AM, Loper JE (1995) The sigma factor σS affects antibiotic production and biological control activity of Pseudomonas fluorescens Pf-5. Proc Natl Acad Sci U S A 92(26):12255–12259

    Article  CAS  Google Scholar 

  • Schanz S, Schroder G, Schroder J (1992) Stilbene synthase from Scots pine (Pinus sylvestris). FEBS Lett 313(1):71–74

    Article  CAS  Google Scholar 

  • Schnider-Keel U, Seematter A, Maurhofer M, Blumer C, Duffy B, Gigot-Bonnefoy C, Reimmann C, Notz R, Defago G, Haas D, Keel C (2000) Autoinduction of 2,4-diacetylphloroglucinol biosynthesis in the biocontrol agent Pseudomonas fluorescens CHA0 and repression by the bacterial metabolites salicylate and pyoluteorin. J Bacteriol 182(5):1215–1225

    Article  CAS  Google Scholar 

  • Schoefer L, Braune A, Blaut M (2004) Cloning and expression of a phloretin hydrolase gene from Eubacterium ramulus and characterization of the recombinant enzyme. Appl Environ Microbiol 70(10):6131–6137

    Article  CAS  Google Scholar 

  • Shanahan P, O’Sullivan DJ, Simpson P, Glennon JD, O’Gara F (1992) Isolation of 2,4-diacetylphloroglucinol from a fluorescent pseudomonad and investigation of physiological parameters influencing its production. Appl Environ Microbiol 58(1):353–358

    CAS  Google Scholar 

  • Silby MW, Cerdeno-Tarraga AM, Vernikos GS, Giddens SR, Jackson RW, Preston GM, Zhang XX, Moon CD, Gehrig SM, Godfrey SAC, Knight CG, Malone JG, Robinson Z, Spiers AJ, Harris S, Challis GL, Yaxley AM, Harris D, Seeger K, Murphy L, Rutter S, Squares R, Quail MA, Saunders E, Mavromatis K, Brettin TS, Bentley SD, Hothersall J, Stephens E, Thomas CM, Parkhill J, Levy SB, Rainey PB, Thomson NR (2009) Genomic and genetic analyses of diversity and plant interactions of Pseudomonas fluorescens. Genome Biol 10(5):R51

    Article  Google Scholar 

  • Singh IP, Bharate SB (2006) Phloroglucinol compounds of natural origin. Nat Prod Rep 23(4):558–591

    Article  CAS  Google Scholar 

  • Singh IP, Sidana J, Bansal P, Foley WJ (2009) Phloroglucinol compounds of therapeutic interest: global patent and technology status. Expert Opin Ther Pat 19(6):847–866

    Article  CAS  Google Scholar 

  • Slininger PJ, Shea-Andersh MA (2005) Proline-based modulation of 2,4-diacetylphloroglucinol and viable cell yields in cultures of Pseudomonas fluorescens wild-type and over-producing strains. Appl Microbiol Biotechnol 68(5):630–638

    Article  CAS  Google Scholar 

  • Sonnleitner E, Haas D (2011) Small RNAs as regulators of primary and secondary metabolism in Pseudomonas species. Appl Microbiol Biotechnol 91(1):63–79

    Article  CAS  Google Scholar 

  • Stirrett K, Denoya C, Westpheling J (2009) Branched-chain amino acid catabolism provides precursors for the type II polyketide antibiotic, actinorhodin, via pathways that are nutrient dependent. J Ind Microbiol Biotechnol 36(1):129–137

    Article  CAS  Google Scholar 

  • Tian T, Wu XG, Duan HM, Zhang LQ (2010) The resistance–nodulation–division efflux pump EmhABC influences the production of 2,4-diacetylphloroglucinol in Pseudomonas fluorescens 2P24. Microbiology-Sgm 156:39–48

    Article  CAS  Google Scholar 

  • Tsay JT, Oh W, Larson TJ, Jackowski S, Rock CO (1992) Isolation and characterization of the β-ketoacyl-acyl carrier protein synthase III gene (fabH) from Escherichia coli K-12. J Biol Chem 267(10):6807–6814

    CAS  Google Scholar 

  • Wang L, Chen H, Zhang T, Zhang J, Yang L (2007) Synthesis, characterization, thermal and explosive properties of potassium salts of trinitrophloroglucinol. J Hazard Mater 147(1–2):576–580

    Article  CAS  Google Scholar 

  • Warshel A, Roca M, Vardi-Kilshtain A (2009) Toward accurate screening in computer-aided enzyme design. Biochemistry 48(14):3046–3056

    Article  Google Scholar 

  • Weller DM, Landa BB, Mavrodi OV, Schroeder KL, Fuente LDL, Bankhead SB, Molar RA, Bonsall RF, Mavrodi DV, Thomashow LS (2007) Role of 2,4-diacetylphloroglucinol-producing fluorescent Pseudomonas spp. in the defense of plant roots. Plant Biology 9(1):4–20

    Article  CAS  Google Scholar 

  • Wu S, Watanabe N, Mita S, Dohra H, Ueda Y, Shibuya M, Ebizuka Y (2004) The key role of phloroglucinol O-methyltransferase in the biosynthesis of rosa chinensis volatile 1,3,5-trimethoxybenzene. Plant Physiol 135(1):95–102

    Article  CAS  Google Scholar 

  • Xiao-Gang W, Hui-Mei D, Tao T, Nan Y, Hong-You Z, Li-Qun Z (2010) Effect of the hfq gene on 2,4-diacetylphloroglucinol production and the PcoI/PcoR quorum-sensing system in Pseudomonas fluorescens 2P24. FEMS Microbiol Lett 309(1):16–24

    Google Scholar 

  • Yuan Z, Cang S, Matsufuji M, Nakata K, Nagamatsu Y, Yoshimoto A (1998) High production of pyoluteorin and 2,4-diacetylphloroglucinol by Pseudomonas fluorescens S272 grown on ethanol as a sole carbon source. J Ferment Bioeng 86(6):559–563

    Article  CAS  Google Scholar 

  • Zha W, Rubin-Pitel SB, Shao Z, Zhao H (2009) Improving cellular malonyl-CoA level in Escherichia coli via metabolic engineering. Metab Eng 11(3):192–198

    Article  CAS  Google Scholar 

  • Zha WJ, Rubin-Pitel SB, Zhao HM (2006) Characterization of the substrate specificity of PhlD, a type III polyketide synthase from Pseudomonas fluorescens. J Biol Chem 281(42):32036–32047

    Article  CAS  Google Scholar 

  • Zha WJ, Rubin-Pitel SB, Zhao HM (2008) Exploiting genetic diversity by directed evolution: molecular breeding of type III polyketide synthases improves productivity. Mol Biosyst 4(3):246–248

    Article  CAS  Google Scholar 

  • Zhou HY, Wei HL, Liu XL, Wang Y, Zhang LQ, Tang WH (2005) Improving biocontrol activity of Pseudomonas fluorescens through chromosomal integration of 2,4-diacetylphloroglucinol biosynthesis genes. Chin Sci Bull 50(8):775–781

    CAS  Google Scholar 

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Yang, F., Cao, Y. Biosynthesis of phloroglucinol compounds in microorganisms—review. Appl Microbiol Biotechnol 93, 487–495 (2012). https://doi.org/10.1007/s00253-011-3712-6

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