A hybrid NRPS-PKS gene cluster related to the bleomycin family of antitumor antibiotics in Alteromonas macleodii strains

PLoS One. 2013 Sep 19;8(9):e76021. doi: 10.1371/journal.pone.0076021. eCollection 2013.

Abstract

Although numerous marine bacteria are known to produce antibiotics via hybrid NRPS-PKS gene clusters, none have been previously described in an Alteromonas species. In this study, we describe in detail a novel hybrid NRPS-PKS cluster identified in the plasmid of the Alteromonasmacleodii strain AltDE1 and analyze its relatedness to other similar gene clusters in a sequence-based characterization. This is a mobile cluster, flanked by transposase-like genes, that has even been found inserted into the chromosome of some Alteromonasmacleodii strains. The cluster contains separate genes for NRPS and PKS activity. The sole PKS gene appears to carry a novel acyltransferase domain, quite divergent from those currently characterized. The predicted specificities of the adenylation domains of the NRPS genes suggest that the final compound has a backbone very similar to bleomycin related compounds. However, the lack of genes involved in sugar biosynthesis indicates that the final product is not a glycopeptide. Even in the absence of these genes, the presence of the cluster appears to confer complete or partial resistance to phleomycin, which may be attributed to a bleomycin-resistance-like protein identified within the cluster. This also suggests that the compound still shares significant structural similarity to bleomycin. Moreover, transcriptomic evidence indicates that the NRPS-PKS cluster is expressed. Such sequence-based approaches will be crucial to fully explore and analyze the diversity and potential of secondary metabolite production, especially from increasingly important sources like marine microbes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alteromonas / classification
  • Alteromonas / genetics*
  • Alteromonas / metabolism*
  • Amino Acids / chemistry
  • Antibiotics, Antineoplastic / biosynthesis*
  • Antibiotics, Antineoplastic / pharmacology
  • Bleomycin / biosynthesis*
  • Bleomycin / pharmacology
  • Drug Resistance, Bacterial / genetics
  • Gene Expression Regulation, Bacterial
  • Gene Order
  • Multigene Family*
  • Peptide Synthases / chemistry
  • Peptide Synthases / genetics*
  • Peptide Synthases / metabolism
  • Phylogeny
  • Polyketide Synthases / chemistry
  • Polyketide Synthases / genetics*
  • Polyketide Synthases / metabolism
  • Protein Interaction Domains and Motifs

Substances

  • Amino Acids
  • Antibiotics, Antineoplastic
  • Bleomycin
  • Polyketide Synthases
  • Peptide Synthases
  • non-ribosomal peptide synthase

Associated data

  • PDB/1MLA
  • PDB/2JFD
  • PDB/3QAT

Grant support

This work was supported by projects MAGYK (BIO2008-02444), MICROGEN (Programa CONSOLIDER-INGENIO 2010 CDS2009-00006), and CGL2009-12651-C02-01 from the Spanish Ministerio de Ciencia e Innovación and by projects DIMEGEN (PROMETEO/2010/089) and ACOMP/2009/155 from the Generalitat Valenciana. FEDER funds and MaCuMBA funds from the European Community (Ref. FP7-KBBE-2012-6-311975) supported this project. R.G. was supported by a Juan de la Cierva scholarship from the Spanish Ministerio de Ciencia e Innovación. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.