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Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria.

Letzel AC, Pidot SJ, Hertweck C - BMC Genomics (2014)

Bottom Line: More than 25% of anaerobes are capable of producing RiPPs either alone or in conjunction with other secondary metabolites, such as polyketides or non-ribosomal peptides.Amongst the analyzed genomes, several gene clusters encode uncharacterized RiPPs, whilst others show similarity with known RiPPs.These include a number of potential class II lanthipeptides; head-to-tail cyclized peptides and lactococcin 972-like RiPP.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Natural Product Research and Infection Biology HKI, Beutenbergstr, 11a, Jena 07745, Germany. christian.hertweck@hki-jena.de.

ABSTRACT

Background: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse group of biologically active bacterial molecules. Due to the conserved genomic arrangement of many of the genes involved in their synthesis, these secondary metabolite biosynthetic pathways can be predicted from genome sequence data. To date, however, despite the myriad of sequenced genomes covering many branches of the bacterial phylogenetic tree, such an analysis for a broader group of bacteria like anaerobes has not been attempted.

Results: We investigated a collection of 211 complete and published genomes, focusing on anaerobic bacteria, whose potential to encode RiPPs is relatively unknown. We showed that the presence of RiPP-genes is widespread among anaerobic representatives of the phyla Actinobacteria, Proteobacteria and Firmicutes and that, collectively, anaerobes possess the ability to synthesize a broad variety of different RiPP classes. More than 25% of anaerobes are capable of producing RiPPs either alone or in conjunction with other secondary metabolites, such as polyketides or non-ribosomal peptides.

Conclusion: Amongst the analyzed genomes, several gene clusters encode uncharacterized RiPPs, whilst others show similarity with known RiPPs. These include a number of potential class II lanthipeptides; head-to-tail cyclized peptides and lactococcin 972-like RiPP. This study presents further evidence in support of anaerobic bacteria as an untapped natural products reservoir.

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Related in: MedlinePlus

Detected putative thiopeptides. A Gene cluster of thiomuracin (tpd) (Nonomuraea str. Bp3714-39) in comparison to putative thiopeptide gene clusters of C. cellulovorans 743B and P. acnes KPA171202; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Comparison of precursor peptides of thiomuracin (TpdA) and putative precursor peptides of C. cellulovorans 753B and P. acnes KPA171202; Cleavage site of leader and core peptide in bold. C Introduction of the central nitrogen heterocycle (red) in series d thiopeptides. D Chemical structure of thiomuracin A.
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Fig7: Detected putative thiopeptides. A Gene cluster of thiomuracin (tpd) (Nonomuraea str. Bp3714-39) in comparison to putative thiopeptide gene clusters of C. cellulovorans 743B and P. acnes KPA171202; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Comparison of precursor peptides of thiomuracin (TpdA) and putative precursor peptides of C. cellulovorans 753B and P. acnes KPA171202; Cleavage site of leader and core peptide in bold. C Introduction of the central nitrogen heterocycle (red) in series d thiopeptides. D Chemical structure of thiomuracin A.

Mentions: Thiopeptides are characterized by a highly modified peptide macrocycle including several thiozole rings, a six-membered nitrogenous ring (either present as piperidine, dehydropiperidine or pyridine) and a side chain containing multiple dehydrated amino acid residues[1, 52, 53]. The introduction of a second macrocycle increases the complexity of these peptides and tryptophan-derived quinaldic acid or indolic acid residues are incorporated into the peptide scaffold. As for LAP biosynthesis, the thiozole rings are formed by dehydrogenation and cyclodehydratation of serine and cysteine residues[1, 52, 53]. The central nitrogen heterocycle is installed by a cycloaddition of two dehydroalanines catalyzed by similar proteins found in lanthipeptide biosynthesis (Figure 7C). Depending on the oxidation state and substitution pattern of the central nitrogen heterocycle, thiopetides are classified into different series (A-E)[1, 52, 53]. Thiomuracin A, isolated from a Nonomuraea species with strong activity against S. aureus[54] (Figure 7D), represents a series D thiopeptide with a tri-substituted pyridine ring as the central nitrogen heterocycle (Figure 7C). Besides the strong activity of many thiopeptides against Gram-positive bacteria by interfering with protein synthesis, some show additional antimalarial or anticancer activities (thiostrepton A)[1, 52, 53].Figure 7


Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria.

Letzel AC, Pidot SJ, Hertweck C - BMC Genomics (2014)

Detected putative thiopeptides. A Gene cluster of thiomuracin (tpd) (Nonomuraea str. Bp3714-39) in comparison to putative thiopeptide gene clusters of C. cellulovorans 743B and P. acnes KPA171202; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Comparison of precursor peptides of thiomuracin (TpdA) and putative precursor peptides of C. cellulovorans 753B and P. acnes KPA171202; Cleavage site of leader and core peptide in bold. C Introduction of the central nitrogen heterocycle (red) in series d thiopeptides. D Chemical structure of thiomuracin A.
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Fig7: Detected putative thiopeptides. A Gene cluster of thiomuracin (tpd) (Nonomuraea str. Bp3714-39) in comparison to putative thiopeptide gene clusters of C. cellulovorans 743B and P. acnes KPA171202; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Comparison of precursor peptides of thiomuracin (TpdA) and putative precursor peptides of C. cellulovorans 753B and P. acnes KPA171202; Cleavage site of leader and core peptide in bold. C Introduction of the central nitrogen heterocycle (red) in series d thiopeptides. D Chemical structure of thiomuracin A.
Mentions: Thiopeptides are characterized by a highly modified peptide macrocycle including several thiozole rings, a six-membered nitrogenous ring (either present as piperidine, dehydropiperidine or pyridine) and a side chain containing multiple dehydrated amino acid residues[1, 52, 53]. The introduction of a second macrocycle increases the complexity of these peptides and tryptophan-derived quinaldic acid or indolic acid residues are incorporated into the peptide scaffold. As for LAP biosynthesis, the thiozole rings are formed by dehydrogenation and cyclodehydratation of serine and cysteine residues[1, 52, 53]. The central nitrogen heterocycle is installed by a cycloaddition of two dehydroalanines catalyzed by similar proteins found in lanthipeptide biosynthesis (Figure 7C). Depending on the oxidation state and substitution pattern of the central nitrogen heterocycle, thiopetides are classified into different series (A-E)[1, 52, 53]. Thiomuracin A, isolated from a Nonomuraea species with strong activity against S. aureus[54] (Figure 7D), represents a series D thiopeptide with a tri-substituted pyridine ring as the central nitrogen heterocycle (Figure 7C). Besides the strong activity of many thiopeptides against Gram-positive bacteria by interfering with protein synthesis, some show additional antimalarial or anticancer activities (thiostrepton A)[1, 52, 53].Figure 7

Bottom Line: More than 25% of anaerobes are capable of producing RiPPs either alone or in conjunction with other secondary metabolites, such as polyketides or non-ribosomal peptides.Amongst the analyzed genomes, several gene clusters encode uncharacterized RiPPs, whilst others show similarity with known RiPPs.These include a number of potential class II lanthipeptides; head-to-tail cyclized peptides and lactococcin 972-like RiPP.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Natural Product Research and Infection Biology HKI, Beutenbergstr, 11a, Jena 07745, Germany. christian.hertweck@hki-jena.de.

ABSTRACT

Background: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse group of biologically active bacterial molecules. Due to the conserved genomic arrangement of many of the genes involved in their synthesis, these secondary metabolite biosynthetic pathways can be predicted from genome sequence data. To date, however, despite the myriad of sequenced genomes covering many branches of the bacterial phylogenetic tree, such an analysis for a broader group of bacteria like anaerobes has not been attempted.

Results: We investigated a collection of 211 complete and published genomes, focusing on anaerobic bacteria, whose potential to encode RiPPs is relatively unknown. We showed that the presence of RiPP-genes is widespread among anaerobic representatives of the phyla Actinobacteria, Proteobacteria and Firmicutes and that, collectively, anaerobes possess the ability to synthesize a broad variety of different RiPP classes. More than 25% of anaerobes are capable of producing RiPPs either alone or in conjunction with other secondary metabolites, such as polyketides or non-ribosomal peptides.

Conclusion: Amongst the analyzed genomes, several gene clusters encode uncharacterized RiPPs, whilst others show similarity with known RiPPs. These include a number of potential class II lanthipeptides; head-to-tail cyclized peptides and lactococcin 972-like RiPP. This study presents further evidence in support of anaerobic bacteria as an untapped natural products reservoir.

Show MeSH
Related in: MedlinePlus