Prodiginines are a family of tripyrrole, red pigments which are attracting increasing interest because of their immunosuppressive and anticancer activities. Currently prodigiosin and a synthetic derivative are in pre-clinical and phase I/II clinical trails, respectively, as treatments for different types of cancer.
Prodiginines are produced by Serratia spp., actinomycetes (for example, Streptomyces coelicolor A3(2)) and various marine bacteria, including Hahella chejuensis KCTC 2396 and Pseudoalteromonas denitrificans. Examples of prodiginines include prodigiosin, undecylprodigiosin and cyclic derivatives such as butyl-meta-cycloheptylprodiginine produced by Streptomyces coelicolor.
As with many secondary metabolites, the true physiological role of prodiginines in the producer organisms is still debated. Suggested roles have included antibacterial, antifungal or trypanolytic agents, aiding surface adherence, enhancing bacterial dispersal and functioning as a metabolic sink.
Biosynthesis of prodiginines proceeds by a bifurcated pathway culminating in the PigC/RedH catalysed condensation of the terminal products of the two pathways, a monopyrrole (2-methyl-3-n-amyl-pyrrole (Serratia) or 2-undecylpyrrole (Streptomyces) and 4-methoxy-2,2′-bipyrrole-5-carbaldehyde (MBC) to form prodigiosin.
A common pathway to the biosynthesis of MBC exists, requiring PigA, PigF, PigG, PigH, PigI, PigJ, PigL, PigM and PigN and their respective S. coelicolor A3(2) homologues. The biosynthesis of the monopyrrroles proceeds by completely different pathways, catalysed by different sets of enzymes.
The first steps in the biosynthesis of MBC have been shown biochemically to involve the incorporation of L-proline to form the pyrrole ring through a pyrrolyl-2-carboxyl-S-PCP intermediate catalysed by RedM, RedO and RedW. This mechanism for the incorporation of proline into a pyrrole is common to many pyrrole-containing compounds, including undecylprodigiosin, prodigiosin, pyoluteorin, coumermycin A1, novobiocin and chlorobiocin.
The production of prodiginines is exquisitely sensitive to numerous environmental and physiological cues, including temperature and carbon source. For example, inorganic phosphate limitation, by the Pho regulon, activates prodiginine synthesis in both Serratia 39006 and S. coelicolor A3(2).
Cell–cell communication by extracellular signalling (quorum sensing) regulates prodiginine biosynthesis by γ-butyrolactones in S. coelicolor A3(2) and N-AHLs, and furanosyl borate diesters or related molecules in Serratia spp. Multiple membrane-associated signalling proteins, including two-component systems, also regulate the production of prodiginines in Serratia 39006 and S. coelicolor A3(2), in response to external signals.
The small, highly phosphorylated nucleotide ppGpp interacts with RNA polymerase to control undecylprodigiosin production in S. coelicolor A3(2) in response to nitrogen starvation. In addition, transcription of the undecylprodigiosin biosynthetic cluster requires two linked pathway-specific activators, RedD and RedZ.
In S. marcescens the modular nature of the prodigiosin biosynthetic loci and the quorum-sensing genes enabled the horizontal transfer of biosynthetic and regulatory loci. This resulted in certain strains immediately acquiring the ability to produce and/or regulate the biosynthesis of this secondary metabolite.
The horizontally mobile nature of prodigiosin production, coupled with the understanding of the substrate flexibility of some of the biosynthetic enzymes, highlights the adaptive plasticity of bacterial secondary metabolism and might enable the evolution and engineering of strains capable of producing a range of prodiginine derivatives with biotechnological uses.
The red-pigmented prodiginines are bioactive secondary metabolites produced by both Gram-negative and Gram-positive bacteria. Recently, these tripyrrole molecules have received renewed attention owing to reported immunosuppressive and anticancer properties. The enzymes involved in the biosynthetic pathways for the production of two of these molecules, prodigiosin and undecylprodigiosin, are now known. However, the biochemistry of some of the reactions is still poorly understood. The physiology and regulation of prodiginine production in Serratia and Streptomyces are now well understood, although the biological role of these pigments in the producer organisms remains unclear. However, research into the biology of pigment production will stimulate interest in the bioengineering of strains to synthesize useful prodiginine derivatives.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Collagen peptide provides Streptomyces coelicolor CGMCC 4.7172 with abundant precursors for enhancing undecylprodigiosin production
Journal of Leather Science and Engineering Open Access 15 July 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Demain, A. L. in Fifty Years of Antimicrobials: Past Perspectives and Future Trends (eds Hunter, P. A., Darby, G. K. & Russell, N. J.) 205–228 (Society for General Microbiology, Cambridge, 1995).
Williams, R. P. & Quadri, S. M. in The Genus Serratia (eds Von Graevenitz, A. & Rubin, S. J.) 31–75 (Boca Raron: CRC Press Inc, 1980).
Kawauchi, K. et al. A possible immunosuppressant, cycloprodigiosin hydrochloride, obtained from Pseudoalteromonas denitrificans. Biochem. Biophys. Res. Commun. 237, 543–547 (1997).
Jeong, H. et al. Genomic blueprint of Hahella chejuensis, a marine microbe producing an algicidal agent. Nucleic Acids Res. 33, 7066–7073 (2005).
Bennett, J. W. & Bentley, R. Seeing red: the story of prodigiosin. Adv. Appl. Microbiol. 47, 1–32 (2000).
Wasserman, H. H., McKeon, J. E. & Smith, L. Prodigiosin. Structure and partial synthesis. J. Am. Chem. Soc. 82, 506–507 (1960).
Rapoport, H. & Holden, H. G. The synthesis of prodigiosin. J. Am. Chem. Soc. 84, 635–642 (1962).
Williams, R. P. Biosynthesis of prodigiosin, a secondary metabolite of Serratia marcescens. Appl. Microbiol. 25, 396–402 (1973). This paper demonstrated that prodigiosin was a secondary metabolite and was one of many important papers on the biosynthesis of prodigiosin by this author.
Gerber, N. N. Prodigiosin-like pigments. CRC Crit. Rev. Microbiol. 3, 469–485 (1975).
Tsao, S. W., Rudd, B. A., He, X. G., Chang, C. J. & Floss, H. G. Identification of a red pigment from Streptomyces coelicolor A3(2) as a mixture of prodigiosin derivatives. J. Antibiot. (Tokyo) 38, 128–131 (1985).
Williamson, N. R. et al. Biosynthesis of the red antibiotic, prodigiosin, in Serratia: identification of a novel 2-methyl-3-n-amyl-pyrrole (MAP) assembly pathway, definition of the terminal condensing enzyme, and implications for undecylprodigiosin biosynthesis in Streptomyces. Mol. Microbiol. 56, 971–989 (2005). This paper described a detailed genetic investigation into the biosynthesis of prodigiosin. Based on LC-MS analyses and cross-feeding of the accumulating intermediates, revised pathways for the biosynthesis of prodigiosin and undecylprodigiosin were proposed.
Purkayastha, M. & Williams, R. P. Association of pigment with the cell envelope of Serratia marcescens (Chromobacterium prodigiosum). Nature 187, 349–350 (1960).
Kobayashi, N. & Ichikawa, Y. A protein associated with prodigiosin formation in Serratia marcescens. Microbiol. Immunol. 33, 257–263 (1989).
Syzdek, L. D. Influence of Serratia marcescens pigmentation on cell concentrations in aerosols produced by bursting bubbles. Appl. Environ. Microbiol. 49, 173–178 (1985).
Burger, S. R. & Bennett, J. W. Droplet enrichment factors of pigmented and nonpigmented Serratia marcescens: possible selective function for prodigiosin. Appl. Environ. Microbiol. 50, 487–490 (1985).
Azambuja, P., Feder, D. & Garcia, E. S. Isolation of Serratia marcescens in the midgut of Rhodnius prolixus: impact on the establishment of the parasite Trypanosoma cruzi in the vector. Exp. Parasitol. 107, 89–96 (2004).
Trutko, S. & Akimenko, V. The role of prodigiosin biosynthesis in the regulation of oxidative metabolism of the producer Serratia marcescens. Mikrobiologiia 58, 723–729 (1989).
Hood, D. W., Heidstra, R., Swoboda, U. K. & Hodgson, D. A. Molecular genetic analysis of proline and tryptophan biosynthesis in Streptomyces coelicolor A3(2): interaction between primary and secondary metabolism — a review. Gene 115, 5–12 (1992).
Williams, R. P., Goldschmidt, M. E. & Gott, C. L. Inhibition by temperature of the terminal step in biosynthesis of prodigiosin. Biochem. Biophys. Res. Commun. 19, 177–181 (1965).
Morrison, D. A. Prodigiosin synthesis in mutants of Serratia marcesens. J. Bacteriol. 91, 1599–1604 (1966).
Goldschmidt, M. C. & Williams, R. P. Thiamine-induced formation of the monopyrrole moiety of prodigiosin. J. Bacteriol. 96, 609–616 (1968).
Feitelson, J. S., Sinha, A. M. & Coco, E. A. Molecular genetics of Red biosynthesis in Streptomyces. J. Nat. Prod. 49, 988–994 (1986).
Feitelson, J. S., Malpartida, F. & Hopwood, D. A. Genetic and biochemical characterization of the red gene cluster of Streptomyces coelicolor A3(2). J. Gen. Microbiol. 131, 2431–2441 (1985).
Feitelson, J. S. & Hopwood, D. A. Cloning of a Streptomyces gene for an O-methyltransferase involved in antibiotic biosynthesis. Mol. Gen. Genet. 190, 394–398 (1983).
Rudd, B. A. & Hopwood, D. A. A pigmented mycelial antibiotic in Streptomyces coelicolor: control by a chromosomal gene cluster. J. Gen. Microbiol. 119, 333–340 (1980).
Malpartida, F., Niemi, J., Navarrete, R. & Hopwood, D. A. Cloning and expression in a heterologous host of the complete set of genes for biosynthesis of the Streptomyces coelicolor antibiotic undecylprodigiosin. Gene 93, 91–99 (1990).
Coco, E. A., Narva, K. E. & Feitelson, J. S. New classes of Streptomyces coelicolor A3(2) mutants blocked in undecylprodigiosin (Red) biosynthesis. Mol. Gen. Genet. 227, 28–32 (1991).
Thomson, N. R., Crow, M. A., McGowan, S. J., Cox, A. & Salmond, G. P. Biosynthesis of carbapenem antibiotic and prodigiosin pigment in Serratia is under quorum sensing control. Mol. Microbiol. 36, 539–556 (2000). This paper reported the cloning and heterologous expression of the Serratia 39006 prodigiosin biosynthetic genes and revealed their regulation by an N -AHL quorum sensing system.
Harris, A. K. et al. The Serratia gene cluster encoding biosynthesis of the red antibiotic, prodigiosin, shows species- and strain-dependent genome context variation. Microbiology 150, 3547–3560 (2004). This paper described the sequencing of two Serratia prodigiosin biosynthetic gene clusters.
Cerdeño, A. M., Bibb, M. J. & Challis, G. L. Analysis of the prodiginine biosynthesis gene cluster of Streptomyces coelicolor A3(2): new mechanisms for chain initiation and termination in modular multienzymes. Chem. Biol. 8, 817–829 (2001). This paper described a detailed sequence analysis of the undecylprodigiosin ( red ) biosynthetic gene cluster.
Fürstner, A. Chemistry and biology of roseophilin and the prodigiosin alkaloids: a survey of the last 2500 years. Angew. Chem. Int. Ed. Engl. 42, 3582–3603 (2003).
Slater, H., Crow, M., Everson, L. & Salmond, G. P. Phosphate availability regulates biosynthesis of two antibiotics, prodigiosin and carbapenem, in Serratia via both quorum-sensing-dependent and -independent pathways. Mol. Microbiol. 47, 303–320 (2003).
Dauenhauer, S. A., Hull, R. A. & Williams, R. P. Cloning and expression in Escherichia coli of Serratia marcescens genes encoding prodigiosin biosynthesis. J. Bacteriol. 158, 1128–1132 (1984).
Wasserman, H. H. et al. Biosynthesis of prodigiosin. Incorporation patterns of C-labeled alanine, proline, glycine, and serine elucidated by fourier transform nuclear magnetic resonance. J. Am. Chem. Soc. 95, 6874–6875 (1973).
Qadri, S. M. & Williams, R. P. Role of methionine in biosynthesis of prodigiosin by Serratia marcescens. J. Bacteriol. 116, 1191–1198 (1973).
Thomas, M. G., Burkart, M. D. & Walsh, C. T. Conversion of L-proline to pyrrolyl-2-carboxyl-S-PCP during undecylprodigiosin and pyoluteorin biosynthesis. Chem. Biol. 9, 171–184 (2002). This paper proved biochemically that the incorporation of L -proline to pyrrolyl-2-carboxyl- S -PCP requires 3 Red proteins (RedO, RedM & RedW). Therefore, this paper described a novel mechanism in pyrrole biosynthesis for the incorporation of L -proline.
Xu, H., Wang, Z. X., Schmidt, J., Heide, L. & Li, S. M. Genetic analysis of the biosynthesis of the pyrrole and carbamoyl moieties of coumermycin A1 and novobiocin. Mol. Genet. Genomics 268, 387–396 (2002).
Walsh, C. T., Garneau-Tsodikova, S. & Howard-Jones, A. R. Biological formation of pyrroles: Nature's logic and enzymatic machinery. Nat. Prod. Rep. 23, 517–531 (2006).
Sunaga, S., Li, H., Sato, Y., Nakagawa, Y. & Matsuyama, T. Identification and characterization of the pswP gene required for the parallel production of prodigiosin and serrawettin W1 in Serratia marcescens. Microbiol. Immunol. 48, 723–728 (2004).
Stanley, A. E., Walton, L. J., Kourdi Zerikly, M., Corre, C. & Challis, G. L. Elucidation of the Streptomyces coelicolor pathway to 4-methoxy-2, 2-bipyrrole-5-carboxaldehyde, an intermediate in prodiginine biosynthesis. Chem. Commun. 3981–3983 (2006). This paper demonstrated the involvement of RedM, RedW, RedX and RedN in the biosynthesis of MBC in S. coelicolor confirming the previously proposed MBC biosynthesis pathway.
Garneau-Tsodikova, S., Dorrestein, P. C., Kelleher, N. L. & Walsh, C. T. Protein assembly line components in prodigiosin biosynthesis: Characterization of PigA, G, H, I, J. J. Am. Chem. Soc. 128, 12600–12601 (2006). In vitro characterization of PigA, PigG, PigH, PigI and PigJ confirming their proposed roles in the biosynthesis of MBC in Serratia.
Mo, S., Kim, B. S. & Reynolds, K. A. Production of branched-chain alkylprodiginines in S. coelicolor by replacement of the 3-ketoacyl ACP synthase III initiation enzyme, RedP. Chem. Biol. 12, 191–200 (2005).
Whitehead, N. A., Barnard, A. M., Slater, H., Simpson, N. J. & Salmond, G. P. Quorum-sensing in Gram-negative bacteria. FEMS Microbiol. Rev. 25, 365–404 (2001).
Fineran, P. C., Slater, H., Everson, L., Hughes, K. & Salmond, G. P. Biosynthesis of tripyrrole and β-lactam secondary metabolites in Serratia: integration of quorum sensing with multiple new regulatory components in the control of prodigiosin and carbapenem antibiotic production. Mol. Microbiol. 56, 1495–1517 (2005). This paper described a complex regulatory network, including quorum sensing, involved in the control of prodigiosin biosynthesis in Serratia 39006.
Horng, Y. T. et al. The LuxR family protein SpnR functions as a negative regulator of N-acylhomoserine lactone-dependent quorum sensing in Serratia marcescens. Mol. Microbiol. 45, 1655–1671 (2002).
Vendeville, A., Winzer, K., Heurlier, K., Tang, C. M. & Hardie, K. R. Making 'sense' of metabolism: autoinducer-2, LuxS and pathogenic bacteria. Nature Rev. Microbiol. 3, 383–396 (2005).
Coulthurst, S. J., Kurz, C. L. & Salmond, G. P. luxS mutants of Serratia defective in autoinducer-2-dependent 'quorum sensing' show strain-dependent impacts on virulence and production of carbapenem and prodigiosin. Microbiology 150, 1901–1910 (2004).
Horinouchi, S. & Beppu, T. A-factor as a microbial hormone that controls cellular differentiation and secondary metabolism in Streptomyces griseus. Mol. Microbiol. 12, 859–864 (1994).
Takano, E. et al. Purification and structural determination of SCB1, a γ-butyrolactone that elicits antibiotic production in Streptomyces coelicolor A3(2). J. Biol. Chem. 275, 11010–11016 (2000).
Takano, E., Chakraburtty, R., Nihira, T., Yamada, Y. & Bibb, M. J. A complex role for the γ-butyrolactone SCB1 in regulating antibiotic production in Streptomyces coelicolor A3(2). Mol. Microbiol. 41, 1015–1028 (2001). This paper reported a γ-butyrolactone signalling system required for the production of undecylprodigiosin in S. coelicolor A3(2).
Onaka, H., Nakagawa, T. & Horinouchi, S. 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 (1998).
Chakraburtty, R. & Bibb, M. The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation. J. Bacteriol. 179, 5854–5861 (1997).
Martinez-Costa, O. H. et al. A relA/spoT homologous gene from Streptomyces coelicolor A3(2) controls antibiotic biosynthetic genes. J. Biol. Chem. 271, 10627–10634 (1996).
Sun, J., Hesketh, A. & Bibb, M. Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2). J. Bacteriol. 183, 3488–3498 (2001).
Ochi, K., Zhang, D., Kawamoto, S. & Hesketh, A. Molecular and functional analysis of the ribosomal L11 and S12 protein genes (rplK and rpsL) of Streptomyces coelicolor A3(2). Mol. Gen. Genet. 256, 488–498 (1997).
Ochi, K. A relaxed (rel) mutant of Streptomyces coelicolor A3(2) with a missing ribosomal protein lacks the ability to accumulate ppGpp, A-factor and prodigiosin. J. Gen. Microbiol. 136, 2405–2412 (1990).
Shima, J., Hesketh, A., Okamoto, S., Kawamoto, S. & Ochi, K. Induction of actinorhodin production by rpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3(2). J. Bacteriol. 178, 7276–7284 (1996).
Magnusson, L. U., Farewell, A. & Nystrom, T. ppGpp: a global regulator in Escherichia coli. Trends Microbiol. 13, 236–242 (2005).
Aigle, B., Wietzorrek, A., Takano, E. & Bibb, M. J. A single amino acid substitution in region 1.2 of the principal sigma factor of Streptomyces coelicolor A3(2) results in pleiotropic loss of antibiotic production. Mol. Microbiol. 37, 995–1004 (2000).
Hu, H., Zhang, Q. & Ochi, K. Activation of antibiotic biosynthesis by specified mutations in the rpoB gene (encoding the RNA polymerase beta subunit) of Streptomyces lividans. J. Bacteriol. 184, 3984–3991 (2002).
Bibb, M. J. Regulation of secondary metabolism in streptomycetes. Curr. Opin. Microbiol. 8, 208–215 (2005).
Takano, E. et al. 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 (1992).
Narva, K. E. & Feitelson, J. S. Nucleotide sequence and transcriptional analysis of the redD locus of Streptomyces coelicolor A3(2). J. Bacteriol. 172, 326–333 (1990).
White, J. & Bibb, M. bldA dependence of undecylprodigiosin production in Streptomyces coelicolor A3(2) involves a pathway-specific regulatory cascade. J. Bacteriol. 179, 627–633 (1997).
Guthrie, E. P. et al. 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, 727–738 (1998).
Guthrie, E. P. & Chater, K. F. The level of a transcript required for production of a Streptomyces coelicolor antibiotic is conditionally dependent on a tRNA gene. J. Bacteriol. 172, 6189–6193 (1990).
Ellison, D. W. & Miller, V. L. Regulation of virulence by members of the MarR/SlyA family. Curr. Opin. Microbiol. 9, 153–159 (2006).
Botsford, J. L. & Harman, J. G. Cyclic AMP in prokaryotes. Microbiol. Rev. 56, 100–122 (1992).
Fineran, P. C., Everson, L., Slater, H. & Salmond, G. P. A GntR family transcriptional regulator (PigT) controls gluconate-mediated repression and defines a new, independent pathway for regulation of the tripyrrole antibiotic, prodigiosin, in Serratia. Microbiology 151, 3833–3845 (2005).
Romling, U., Gomelsky, M. & Galperin, M. Y. C-di-GMP: the dawning of a novel bacterial signalling system. Mol. Microbiol. 57, 629–639 (2005).
Harris, S. J., Shih, Y. L., Bentley, S. D. & Salmond, G. P. The hexA gene of Erwinia carotovora encodes a LysR homologue and regulates motility and the expression of multiple virulence determinants. Mol. Microbiol. 28, 705–717 (1998).
Tanikawa, T., Nakagawa, Y. & Matsuyama, T. Transcriptional downregulator HexS controlling prodigiosin and serrawettin W1 biosynthesis in Serratia marcescens. Microbiol. Immunol. 50, 587–596 (2006).
Heeb, S. & Haas, D. Regulatory roles of the GacS/GacA two-component system in plant- associated and other Gram-negative bacteria. Mol. Plant Microbe Interact. 14, 1351–1363 (2001).
Suzuki, K. et al. Regulatory circuitry of the CsrA/CsrB and BarA/UvrY systems of Escherichia coli. J. Bacteriol. 184, 5130–5140 (2002).
Romeo, T. Global regulation by the small RNA-binding protein CsrA and the non-coding RNA molecule CsrB. Mol. Microbiol. 29, 1321–1330 (1998).
Ang, S. et al. The role of RsmA in the regulation of swarming motility in Serratia marcescens. J. Biomed. Sci. 8, 160–169 (2001).
Ishizuka, H., Horinouchi, S., Kieser, H. M., Hopwood, D. A. & Beppu, T. A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J. Bacteriol. 174, 7585–7594 (1992).
Li, Y. Q., Chen, P. L., Chen, S. F., Wu, D. & Zheng, J. A pair of two-component regulatory genes ecrA1/A2 in S. coelicolor. J. Zhejiang. Univ. Sci. 5, 173–179 (2004).
Huang, J., Lih, C. J., Pan, K. H. & Cohen, S. N. 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 (2001). This paper discusses the global transcriptomic analysis of antibiotic biosynthesis in S. coelicolor . Biosynthetic loci were confirmed by cluster analysis and both previously characterized and novel undecylprodigiosin regulators were identified.
Anderson, T. B., Brian, P. & Champness, W. C. Genetic and transcriptional analysis of absA, an antibiotic gene cluster-linked two-component system that regulates multiple antibiotics in Streptomyces coelicolor. Mol. Microbiol. 39, 553–566 (2001).
Sheeler, N. L., MacMillan, S. V. & Nodwell, J. R. Biochemical activities of the absA two-component system of Streptomyces coelicolor. J. Bacteriol. 187, 687–696 (2005).
Aceti, D. J. & Champness, W. C. Transcriptional regulation of Streptomyces coelicolor pathway-specific antibiotic regulators by the absA and absB loci. J. Bacteriol. 180, 3100–3106 (1998).
Adamidis, T., Riggle, P. & Champness, W. Mutations in a new Streptomyces coelicolor locus which globally block antibiotic biosynthesis but not sporulation. J. Bacteriol. 172, 2962–2969 (1990).
Horinouchi, S. AfsR as an integrator of signals that are sensed by multiple serine/threonine kinases in Streptomyces coelicolor A3(2). J. Ind. Microbiol. Biotechnol. 30, 462–467 (2003). This review summarized research on the S. coelicolor AfsR undecylprodigiosin regulator. This system was the first example of serine/threonine kinases in bacteria.
Sawai, R., Suzuki, A., Takano, Y., Lee, P. C. & Horinouchi, S. Phosphorylation of AfsR by multiple serine/threonine kinases in Streptomyces coelicolor A3(2). Gene 334, 53–61 (2004).
Sola-Landa, A., Moura, R. S. & Martin, J. F. 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 (2003).
Martin, J. F. 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 (2004).
Chouayekh, H. & Virolle, M. J. The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans. Mol. Microbiol. 43, 919–930 (2002).
Sevcikova, B. & Kormanec, J. Differential production of two antibiotics of Streptomyces coelicolor A3(2), actinorhodin and undecylprodigiosin, upon salt stress conditions. Arch. Microbiol. 181, 384–389 (2004).
Stoyanov, J. V., Hobman, J. L. & Brown, N. L. CueR (YbbI) of Escherichia coli is a MerR family regulator controlling expression of the copper exporter CopA. Mol. Microbiol. 39, 502–511 (2001).
Williamson, N. R., Simonsen, H. T., Harris, A. K., Leeper, F. J. & Salmond, G. P. Disruption of the copper efflux pump (CopA) of Serratia marcescens ATCC 274 pleiotropically affects copper sensitivity and production of the tripyrrole secondary metabolite, prodigiosin. J. Ind. Microbiol. Biotechnol. 33, 151–158 (2006).
Coulthurst, S. J., Williamson, N. R., Harris, A. K., Spring, D. R. & Salmond, G. P. Metabolic and regulatory engineering of Serratia marcescens: mimicking phage-mediated horizontal acquisition of antibiotic biosynthesis and quorum-sensing capacities. Microbiology 152, 1899–1911 (2006). The horizontally mobile modular nature of the prodigiosin biosynthetic loci and their quorum sensing regulators was demonstrated in S. marcescens , highlighting the adaptive flexibility of bacterial secondary metabolism.
Wei, J. R. et al. A mobile quorum-sensing system in Serratia marcescens. J. Bacteriol. 188, 1518–1525 (2006).
Firn, R. D. & Jones, C. G. The evolution of secondary metabolism — a unifying model. Mol. Microbiol. 37, 989–994 (2000).
Demain, A. L. Pharmaceutically active secondary metabolites of microorganisms. Appl. Microbiol. Biotechnol. 52, 455–463 (1999).
Pérez-Tomás, R., Montaner, B., Llagostera, E. & Soto-Cerrato, V. The prodigiosins, proapoptotic drugs with anticancer properties. Biochem. Pharmacol. 66, 1447–1452 (2003). This review provided an overview of a large body of research on the pro-apoptotic and anticancer properties of prodigiosins.
Mortellaro, A. et al. New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. J. Immunol. 162, 7102–7109 (1999).
Han, S. B. et al. Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen- induced arthritis. J. Pharmacol. Exp. Ther. 299, 415–425 (2001).
D'Alessio, R. et al. Synthesis and immunosuppressive activity of novel prodigiosin derivatives. J. Med. Chem. 43, 2557–2565 (2000).
Han, S. B. et al. T-cell specific immunosuppression by prodigiosin isolated from Serratia marcescens. Int. J. Immunopharmacol. 20, 1–13 (1998).
Han, S. B. et al. Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A. Biochem. Pharmacol. 70, 1518–1526 (2005).
Stepkowski, S. M. et al. Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood 99, 680–689 (2002).
Llagostera, E., Soto-Cerrato, V., Montaner, B. & Pérez-Tomás, R. Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer cells. Ann. NY Acad. Sci. 1010, 178–181 (2003).
Soto-Cerrato, V., Llagostera, E., Montaner, B., Scheffer, G. L. & Pérez-Tomás, R. Mitochondria-mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin. Biochem. Pharmacol. 68, 1345–1352 (2004).
Zhang, J., Shen, Y., Liu, J. & Wei, D. Antimetastatic effect of prodigiosin through inhibition of tumor invasion. Biochem. Pharmacol. 69, 407–414 (2005).
Manderville, R. A. Synthesis, proton-affinity and anti-cancer properties of the prodigiosin-group natural products. Curr. Med. Chem. Anti-Canc. Agents. 1, 195–218 (2001).
Montaner, B. et al. DNA interaction and dual topoisomerase I and II inhibition properties of the anti-tumor drug prodigiosin. Toxicol. Sci. 85, 870–879 (2005).
Fürstner, A., Reinecke, K., Prinz, H. & Waldmann, H. The core structures of roseophilin and the prodigiosin alkaloids define a new class of protein tyrosine phosphatase inhibitors. Chembiochem. 5, 1575–1579 (2004).
Berg, G. Diversity of antifungal and plant-associated Serratia plymuthica strains. J. Appl. Microbiol. 88, 952–960 (2000).
Liu, R., Cui, C. B., Duan, L., Gu, Q. Q. & Zhu, W. M. Potent in vitro anticancer activity of metacycloprodigiosin and undecylprodigiosin from a sponge-derived actinomycete Saccharopolyspora sp. nov. Arch. Pharm. Res. 28, 1341–1344 (2005).
Adamidis, T. & Champness, W. Genetic analysis of absB, a Streptomyces coelicolor locus involved in global antibiotic regulation. J. Bacteriol. 174, 4622–4628 (1992).
Champness, W., Riggle, P., Adamidis, T. & Vandervere, P. Identification of Streptomyces coelicolor genes involved in regulation of antibiotic synthesis. Gene 115, 55–60 (1992).
Hunt, A. C., Servin-Gonzalez, L., Kelemen, G. H. & Buttner, M. J. The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family. J. Bacteriol. 187, 716–728 (2005).
Cho, Y. H., Lee, E. J., Ahn, B. E. & Roe, J. H. SigB, an RNA polymerase sigma factor required for osmoprotection and proper differentiation of Streptomyces coelicolor. Mol. Microbiol. 42, 205–214 (2001).
Schneider, D., Bruton, C. J. & Chater, K. F. Characterization of spaA, a Streptomyces coelicolor gene homologous to a gene involved in sensing starvation in Escherichia coli. Gene 177, 243–251 (1996).
Yonekawa, T., Ohnishi, Y. & Horinouchi, S. Involvement of amfC in physiological and morphological development in Streptomyces coelicolor A3(2). Microbiology 145, 2273–2280 (1999).
Shima, J., Penyige, A. & Ochi, K. Changes in patterns of ADP-ribosylated proteins during differentiation of Streptomyces coelicolor A3(2) and its development mutants. J. Bacteriol. 178, 3785–3790 (1996).
Fernandez-Moreno, M. A. et al. abaA, a new pleiotropic regulatory locus for antibiotic production in Streptomyces coelicolor. J. Bacteriol. 174, 2958–2967 (1992).
Scheu, A. K., Martinez, E., Soliveri, J. & Malpartida, F. abaB, a putative regulator for secondary metabolism in Streptomyces. FEMS Microbiol. Lett. 147, 29–36 (1997).
Umeyama, T., Tanabe, Y., Aigle, B. D. & Horinouchi, S. Expression of the Streptomyces coelicolor A3(2) ptpA gene encoding a phosphotyrosine protein phosphatase leads to overproduction of secondary metabolites in S. lividans. FEMS Microbiol. Lett. 144, 177–184 (1996).
Süsstrunk, U., Pidoux, J., Taubert, S., Ullmann, A. & Thompson, C. J. Pleiotropic effects of cAMP on germination, antibiotic biosynthesis and morphological development in Streptomyces coelicolor. Mol. Microbiol. 30, 33–46 (1998).
Yu, V. L. Serratia marcescens: historical perspective and clinical review. N. Engl. J. Med. 300, 887–893 (1979).
Cullen, J. C. in ASM News 187–191 (1994).
Hubbard, R. & Rimington, C. The biosynthesis of prodigiosin, the tripyrrylmethene pigment fromBacillus prodigiosus (Serratia marcescens). Biochem. J. 46, 220–225 (1950).
Dairi, K., Tripathy, S., Attardo, G. & Lavallee, J. F. Two-step synthesis of the bipyrrole precursor of prodigiosins. Tetrahedron Lett. 47, 2605–2606 (2006).
Work in the authors' laboratories is generously funded by the Biotechnology and Biological Sciences Research Council, UK. P.F.'s Ph.D. research on prodigiosin was supported by a Bright Futures Top Achiever Doctoral Scholarship from the tertiary education commission of New Zealand.
The authors declare no competing financial interests.
About this article
Cite this article
Williamson, N., Fineran, P., Leeper, F. et al. The biosynthesis and regulation of bacterial prodiginines. Nat Rev Microbiol 4, 887–899 (2006). https://doi.org/10.1038/nrmicro1531
This article is cited by
Applied Microbiology and Biotechnology (2022)
New Report: Genome Mining Untaps the Antibiotics Biosynthetic Gene Cluster of Pseudoalteromonas xiamenensis STKMTI.2 from a Mangrove Soil Sediment
Marine Biotechnology (2022)
Collagen peptide provides Streptomyces coelicolor CGMCC 4.7172 with abundant precursors for enhancing undecylprodigiosin production
Journal of Leather Science and Engineering (2021)
Comparative transcriptome analysis reveals metabolic regulation of prodigiosin in Serratia marcescens
Systems Microbiology and Biomanufacturing (2021)
GABA-producing Lactobacillus plantarum inhibits metastatic properties and induces apoptosis of 5-FU-resistant colorectal cancer cells via GABAB receptor signaling
Journal of Microbiology (2021)