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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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Detected putative sactipeptides. A Thuricidin CD gene cluster (tm) of B. thuringiensis DPC 6431 and subtilosin A gene cluster (alb) of B. subtilis 168 in comparison to detected putative sactipeptide gene clusters; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Amino acid structure of thuricin CD α-subunit (Trnα) C Characteristic sulfur bridge between a cysteine residue and the α-carbon of another residue in sactipeptides.
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Fig5: Detected putative sactipeptides. A Thuricidin CD gene cluster (tm) of B. thuringiensis DPC 6431 and subtilosin A gene cluster (alb) of B. subtilis 168 in comparison to detected putative sactipeptide gene clusters; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Amino acid structure of thuricin CD α-subunit (Trnα) C Characteristic sulfur bridge between a cysteine residue and the α-carbon of another residue in sactipeptides.

Mentions: Sactipeptides or sactibiotics (sulphur to alpha-carbon antibiotic) are peptides in which a sulfur bridge is post-translationally formed between a cysteine residue and the α-carbon of another residue (Figure 5B & C), in contrast to lanthipeptides where the sulfur bridge is installed via the β-carbon[1, 34]. The sulfur linkage is introduced via a special radical SAM enzyme whose gene is co-localized in all sactipetide gene clusters and can be used for genome mining approaches[1, 35–37]. Several sactipeptides have so far been elucidated, all from Bacillus species, and include subtilosin A (B. subtilis, hemolytic)[38, 39], thuricin CD with its components Trn-α and Trn-β (B. thuringiensis, anticlostridial)[40], thurincin H (B. thuringiensis)[41] and the sporulation killing factor (SKF) (B. subtilis)[42]. Approximately 0.5% of the total protein content of anaerobic bacteria is represented by highly diverse radical SAM enzymes[43], and using putative radical SAM enzymes as a means of identifying sactipeptide loci returned a large number of enzymes putatively involved in RiPP formation. A similar approach was previously taken by Murphy et al., using the radical SAM enzyme of the thuricin CD gene cluster as BLAST template, which identified several thuricin CD-like biosynthetic gene clusters, including several in anaerobic bacteria[37].Figure 5


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 sactipeptides. A Thuricidin CD gene cluster (tm) of B. thuringiensis DPC 6431 and subtilosin A gene cluster (alb) of B. subtilis 168 in comparison to detected putative sactipeptide gene clusters; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Amino acid structure of thuricin CD α-subunit (Trnα) C Characteristic sulfur bridge between a cysteine residue and the α-carbon of another residue in sactipeptides.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289311&req=5

Fig5: Detected putative sactipeptides. A Thuricidin CD gene cluster (tm) of B. thuringiensis DPC 6431 and subtilosin A gene cluster (alb) of B. subtilis 168 in comparison to detected putative sactipeptide gene clusters; Numbers represent the locus tag for each gene within the genome sequence of each organism. B Amino acid structure of thuricin CD α-subunit (Trnα) C Characteristic sulfur bridge between a cysteine residue and the α-carbon of another residue in sactipeptides.
Mentions: Sactipeptides or sactibiotics (sulphur to alpha-carbon antibiotic) are peptides in which a sulfur bridge is post-translationally formed between a cysteine residue and the α-carbon of another residue (Figure 5B & C), in contrast to lanthipeptides where the sulfur bridge is installed via the β-carbon[1, 34]. The sulfur linkage is introduced via a special radical SAM enzyme whose gene is co-localized in all sactipetide gene clusters and can be used for genome mining approaches[1, 35–37]. Several sactipeptides have so far been elucidated, all from Bacillus species, and include subtilosin A (B. subtilis, hemolytic)[38, 39], thuricin CD with its components Trn-α and Trn-β (B. thuringiensis, anticlostridial)[40], thurincin H (B. thuringiensis)[41] and the sporulation killing factor (SKF) (B. subtilis)[42]. Approximately 0.5% of the total protein content of anaerobic bacteria is represented by highly diverse radical SAM enzymes[43], and using putative radical SAM enzymes as a means of identifying sactipeptide loci returned a large number of enzymes putatively involved in RiPP formation. A similar approach was previously taken by Murphy et al., using the radical SAM enzyme of the thuricin CD gene cluster as BLAST template, which identified several thuricin CD-like biosynthetic gene clusters, including several in anaerobic bacteria[37].Figure 5

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