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

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 activities of these analogues were evaluated.

• Authors: Yuquan Xu, E M Kithsiri Wijeratne, Patricia Espinosa-Artiles, A A Leslie Gunatilaka, István Molnár
• Journal: Chembiochem : a European journal of chemical biology (Chembiochem) Vol. 10 Issue 2 Pg. 345-54 (Jan 26 2009) ISSN: 1439-7633 [Electronic] Germany
• PMID: 19105175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Depsipeptides
• Peptides, Cyclic
• Valerates
• beauvericin
• Phenindione
• bassianolide
• Ketone Oxidoreductases
• 2-ketoisovalerate ferredoxin oxidoreductase

Topics

• Amino Acid Sequence
• Beauveria (genetics, metabolism)
• Cell Movement (drug effects)
• Cloning, Molecular
• Depsipeptides (biosynthesis, chemistry, pharmacology)
• Gene Knockout Techniques
• Genetic Engineering (methods)
• Ketone Oxidoreductases (chemistry, genetics, metabolism)
• Molecular Sequence Data
• Peptides, Cyclic (biosynthesis)
• Phenindione (metabolism)
• Sequence Analysis, DNA
• Valerates (chemistry, metabolism)