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The biosynthesis and regulation of bacterial prodiginines

Key Points

  • 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.

Abstract

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.

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Figure 1: Comparison of prodiginine biosynthetic gene clusters.
Figure 2: Examples of cross-feeding.
Figure 3: The bifurcated biosynthetic pathway of the prodiginines.
Figure 4: Summary of the genetic regulation of prodigiosin production in Serratia species.
Figure 5: Summary of the genetic regulation of undecylprodigiosin production in Streptomyces coelicolor A3(2).

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Acknowledgements

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.

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DATABASES

Entrez Genome Project

Escherichia coli

Hahella chejuensisKCTC 2396

Serratia marcescens

Streptomyces coelicolorA3(2)

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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

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