Generation of new landomycins with altered saccharide patterns through over-expression of the glycosyltransferase gene lanGT3 in the biosynthetic gene cluster of landomycin A in Streptomyces cyanogenus S-136

Lili Zhu, Andriy Luzhetskyy, Martha Luzhetska, Cynthia Mattingly, Val Adams, Andreas Bechthold, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Two novel landomycin compounds, landomycins I and J, were generated with a new mutant strain of Streptomyces cyanogenus in which the glycosyltransferase that is encoded by lanGT3 was over-expressed. This mutant also produced the known landomycins A, B, and D, All these compounds consist of the same polyketide-derived aglycon but differ in their sugar moieties, which are chains of different lengths. The major new metabolite, landomycin J, was found to consist of landomycinone with a tetrasaccharide chain attached. Combined with previous results of the production of landomycin E (which contains three sugars) by the LanGT3 mutant strain (obtained by targeted gene deletion of lanGT3), it was verified that LanGT3 is a D-olivosyltransferase responsible for the transfer of the fourth sugar required for landomycin A biosynthesis. The experiments also showed that gene over-expression is a powerful method for unbalancing biosynthetic pathways in order to generate new metabolites. The cytotoxicity of the new landomycins-compared to known ones-was assessed by using three different tumor cell lines, and their structure-activity relationship (SAR) with respect to the length of the deoxysugar side chain was deduced from the results.

Original languageEnglish
Pages (from-to)83-88
Number of pages6
JournalChemBioChem
Volume8
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Biosynthesis
  • Combinatorial biosynthesis glycosylation
  • Landomycins
  • Polyketides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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