Combinatorial mutasynthesis of scrambled beauvericins, cyclooligomer depsipeptide cell migration inhibitors from Beauveria bassiana

Yuquan Xu, E. M.Kithsiri Wijeratne, Patricia Espinosa-Artiles, A. A.Leslie Gunatilaka, István Molnár

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Fungal cyclooligomer depsipeptides such as beauvericin, bassianolide, and enniatins display antibiotic, antifungal, insecticidal, broad-spectrum cancer cell antiproliferative, and cell migration inhibitory activities. We have identified a gene encoding a novel enzyme, ketoisovalerate reductase (KIVR), which is the sole provider of D-hydroxyisovalerate (D-Hiv), a common precursor for cyclooligomer depsipeptide biosynthesis in Beauveria bassiana. KIVR and related hypothetical oxidoreductases encoded in fungal genomes are similar to ketopantoate reductases but not to D-hydroxycarboxylate dehydrogenases. We demonstrate that a KIVR knockout B. bassiana strain can be used for the efficient mutasynthesis of unnatural beauvericin congeners. Simultaneous feeding of precursor analogues enabled the combinatorial mutasynthesis of scrambled beauvericins, some assembled entirely from unnatural precursors. The effects of the introduced structural changes on the antiproliferative and cell migration inhibitory ACHTUNGTRENNUNGactivities of these analogues were evaluated.

Original languageEnglish (US)
Pages (from-to)345-354
Number of pages10
JournalChemBioChem
Volume10
Issue number2
DOIs
StatePublished - Jan 26 2009

Keywords

  • Antitumor agents
  • Beauveria
  • Beauvericin
  • Biosynthesis
  • Mutasynthesis
  • Nonribosomal peptide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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