New Rimocidin/CE-108 Derivatives Obtained by a Crotonyl-CoA Carboxylase/Reductase Gene Disruption in Streptomyces diastaticus var. 108: Substrates for the Polyene Carboxamide Synthase PcsA

PLoS One. 2015 Aug 18;10(8):e0135891. doi: 10.1371/journal.pone.0135891. eCollection 2015.

Abstract

The rimJ gene, which codes for a crotonyl-CoA carboxylase/reductase, lies within the biosynthetic gene cluster for two polyketides belonging to the polyene macrolide group (CE-108 and rimocidin) produced by Streptomyces diastaticus var. 108. Disruption of rimJ by insertional inactivation gave rise to a recombinant strain overproducing new polyene derivatives besides the parental CE-108 (2a) and rimocidin (4a). The structure elucidation of one of them, CE-108D (3a), confirmed the incorporation of an alternative extender unit for elongation step 13. Other compounds were also overproduced in the fermentation broth of rimJ disruptant. The new compounds are in vivo substrates for the previously described polyene carboxamide synthase PcsA. The rimJ disruptant strain, constitutively expressing the pcsA gene, allowed the overproduction of CE-108E (3b), the corresponding carboxamide derivative of CE-108D (3a), with improved pharmacological properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amide Synthases / metabolism*
  • Carbon-Carbon Ligases / genetics*
  • Carbon-Carbon Ligases / metabolism
  • Genetic Engineering*
  • Macrolides / chemistry
  • Macrolides / metabolism*
  • Monosaccharides / chemistry
  • Monosaccharides / metabolism*
  • Polyenes / chemistry
  • Polyenes / metabolism
  • Streptomyces / enzymology
  • Streptomyces / genetics*
  • Streptomyces / metabolism
  • Substrate Specificity

Substances

  • CE-108
  • Macrolides
  • Monosaccharides
  • Polyenes
  • rimocidin
  • Amide Synthases
  • Carbon-Carbon Ligases

Grants and funding

This work was supported by grants to F.M. from the Spanish Ministerio de Ciencia e Innovación BIO2005-02785 and BIO2008-03683, and to J.C.A. from Spanish Ministerio de Economía y Competitividad BFU2012-39879-C02-01. The German Academic Exchange Service (DAAD) supported M.A.R. with a Ph.D. grant.