1887

Abstract

Streptomyces species and other Actinobacteria are ubiquitous in diverse environments worldwide and are the source of, or inspiration for, the majority of antibiotics. The genomic era has enhanced biosynthetic understanding of these valuable chemical entities and has also provided a window into the diversity and distribution of natural product biosynthetic gene clusters. Antimycin is an inhibitor of mitochondrial cytochrome c reductase and more recently was shown to inhibit Bcl-2/Bcl-XL-related anti-apoptotic proteins commonly overproduced by cancerous cells. Here we identify 73 putative antimycin biosynthetic gene clusters (BGCs) in publicly available genome sequences of Actinobacteria and classify them based on the presence or absence of cluster-situated genes antP and antQ, which encode a kynureninase and a phosphopantetheinyl transferase (PPTase), respectively. The majority of BGCs possess either both antP and antQ (L-form) or neither (S-form), while a minority of them lack either antP or antQ (IQ- or IP-form, respectively). We also evaluate the biogeographical distribution and phylogenetic relationships of antimycin producers and BGCs. We show that antimycin BGCs occur on five of the seven continents and are frequently isolated from plants and other higher organisms. We also provide evidence for two distinct phylogenetic clades of antimycin producers and gene clusters, which delineate S-form from L- and I-form BGCs. Finally, our findings suggest that the ancestral antimycin producer harboured an L-form gene cluster which was primarily propagated by vertical transmission and subsequently diversified into S-, IQ- and IP-form biosynthetic pathways.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000572
2017-11-07
2019-09-24
Loading full text...

Full text loading...

/deliver/fulltext/micro/164/1/28.html?itemId=/content/journal/micro/10.1099/mic.0.000572&mimeType=html&fmt=ahah

References

  1. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012;75:311–335 [CrossRef][PubMed]
    [Google Scholar]
  2. Jensen PR. Natural products and the gene cluster revolution. Trends Microbiol 2016;24:968–977 [CrossRef][PubMed]
    [Google Scholar]
  3. Liu J, Zhu X, Kim SJ, Zhang W. Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities. Nat Prod Rep 2016;33:1146–1165 [CrossRef][PubMed]
    [Google Scholar]
  4. Dunshee BR, Leben C, Keitt GW, Strong FM. The isolation and properties of antimycin A. J Am Chem Soc 1949;71:2436–2437 [CrossRef]
    [Google Scholar]
  5. Ueda JY, Nagai A, Izumikawa M, Chijiwa S, Takagi M et al. A novel antimycin-like compound, JBIR-06, from Streptomyces sp. ML55. J Antibiot 2008;61:241–244 [CrossRef][PubMed]
    [Google Scholar]
  6. Caglioti L, Misiti D, Mondelli R, Selva A, Arcamone F et al. The structure of neoantimycin. Tetrahedron 1969;25:2193–2221 [CrossRef][PubMed]
    [Google Scholar]
  7. Urushibata I, Isogai A, Matsumoto S, Suzuki A. Respirantin, a novel insecticidal cyclodepsipeptide from Streptomyces. J Antibiot 1993;46:701–703 [CrossRef][PubMed]
    [Google Scholar]
  8. Tappel AL. Inhibition of electron transport by antimycin A, alkyl hydroxy naphthoquinones and metal coordination compounds. Biochem Pharmacol 1960;3:289–296 [CrossRef][PubMed]
    [Google Scholar]
  9. Tzung SP, Kim KM, Basañez G, Giedt CD, Simon J et al. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. 2001;3183–191
  10. Seipke RF, Barke J, Brearley C, Hill L, Yu DW et al. A single Streptomyces symbiont makes multiple antifungals to support the fungus farming ant Acromyrmex octospinosus. PLoS One 2011;6:e220288 [CrossRef][PubMed]
    [Google Scholar]
  11. Seipke RF, Patrick E, Hutchings MI. Regulation of antimycin biosynthesis by the orphan ECF RNA polymerase sigma factor σ (AntA.). PeerJ 2014;2:e253 [CrossRef][PubMed]
    [Google Scholar]
  12. Sandy M, Rui Z, Gallagher J, Zhang W. Enzymatic synthesis of dilactone scaffold of antimycins. ACS Chem Biol 2012;7:1956–1961 [CrossRef][PubMed]
    [Google Scholar]
  13. Sandy M, Zhu X, Rui Z, Zhang W. Characterization of AntB, a promiscuous acyltransferase involved in antimycin biosynthesis. Org Lett 2013;15:3396–3399 [CrossRef][PubMed]
    [Google Scholar]
  14. Liu J, Zhu X, Seipke RF, Zhang W. Biosynthesis of antimycins with a reconstituted 3-formamidosalicylate pharmacophore in Escherichia coli. ACS Synth Biol 2015;4:559–565 [CrossRef][PubMed]
    [Google Scholar]
  15. Mclean TC, Hoskisson PA, Seipke RF. Coordinate regulation of antimycin and candicidin biosynthesis. mSphere 2016;1:e00305-16 [CrossRef][PubMed]
    [Google Scholar]
  16. Schoenian I, Paetz C, Dickschat JS, Aigle B, Leblond P et al. An unprecedented 1,2-shift in the biosynthesis of the 3-aminosalicylate moiety of antimycins. Chembiochem 2012;13:769–773 [CrossRef][PubMed]
    [Google Scholar]
  17. Seipke RF, Hutchings MI. The regulation and biosynthesis of antimycins. Beilstein J Org Chem 2013;9:2556–2563 [CrossRef][PubMed]
    [Google Scholar]
  18. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014;30:2068–2069 [CrossRef][PubMed]
    [Google Scholar]
  19. Medema MH, Takano E, Breitling R. Detecting sequence homology at the gene cluster level with MultiGeneBlast. Mol Biol Evol 2013;30:1218–1223 [CrossRef][PubMed]
    [Google Scholar]
  20. Kurtz S, Phillippy A, Delcher AL, Smoot M, Shumway M et al. Versatile and open software for comparing large genomes. Genome Biol 2004;5:R12 [CrossRef][PubMed]
    [Google Scholar]
  21. Darling AE, Jospin G, Lowe E, Matsen FA, Bik HM et al. PhyloSift: phylogenetic analysis of genomes and metagenomes. PeerJ 2014;2:e24328 [CrossRef][PubMed]
    [Google Scholar]
  22. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004;32:1792–1797 [CrossRef][PubMed]
    [Google Scholar]
  23. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 2010;59:307–321 [CrossRef][PubMed]
    [Google Scholar]
  24. Ziemert N, Lechner A, Wietz M, Millán-Aguiñaga N, Chavarria KL et al. Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proc Natl Acad Sci USA 2014;111:E1130E1139 [CrossRef][PubMed]
    [Google Scholar]
  25. Maddison WP, Maddison DR. Mesquite: a modular system for evolutionary analysis. Version3.2. 2017;http://mesquiteproject.org
  26. Seipke RF. Strain-level diversity of secondary metabolism in Streptomyces albus. PLoS One 2015;10:e011645714 [CrossRef][PubMed]
    [Google Scholar]
  27. Bunet R, Riclea R, Laureti L, Hôtel L, Paris C et al. A single Sfp-type phosphopantetheinyl transferase plays a major role in the biosynthesis of PKS and NRPS derived metabolites in Streptomyces ambofaciens ATCC23877. PLoS One 2014;9:e87607 [CrossRef][PubMed]
    [Google Scholar]
  28. Reddy BV, Milshteyn A, Charlop-Powers Z, Brady SF. eSNaPD: a versatile, web-based bioinformatics platform for surveying and mining natural product biosynthetic diversity from metagenomes. Chem Biol 2014;21:1023–1033 [CrossRef][PubMed]
    [Google Scholar]
  29. Seipke RF, Kaltenpoth M, Hutchings MI. Streptomyces as symbionts: an emerging and widespread theme?. FEMS Microbiol Rev 2012;36:862–876 [CrossRef][PubMed]
    [Google Scholar]
  30. Flórez LV, Biedermann PH, Engl T, Kaltenpoth M. Defensive symbioses of animals with prokaryotic and eukaryotic microorganisms. Nat Prod Rep 2015;32:904–936 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000572
Loading
/content/journal/micro/10.1099/mic.0.000572
Loading

Data & Media loading...

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error