Combinatorial mutasynthesis of scrambled beauvericins, cyclooligomer depsipeptide cell migration inhibitors from Beauveria bassiana.
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.
Xu
Yuquan
Y
SW Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, The University of Arizona, 250 E. Valencia Rd., Tucson, AZ 85706-6800, USA.
Wijeratne
E M Kithsiri
EM
Espinosa-Artiles
Patricia
P
Gunatilaka
A A Leslie
AA
Molnár
István
I
D000595:Amino Acid Sequence; D052982:Beauveria / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D003001:Cloning, Molecular; D047630:Depsipeptides / Q000096:biosynthesis* / Q000737:chemistry* / Q000494:pharmacology; D055786:Gene Knockout Techniques; D005818:Genetic Engineering / Q000379:methods*; D007658:Ketone Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000096:biosynthesis; D010630:Phenindione / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014631:Valerates / Q000737:chemistry / Q000378:metabolism
D047630:Depsipeptides; D010456:Peptides, Cyclic; D014631:Valerates; C004456:beauvericin; D010630:Phenindione; C035050:bassianolide; D007658:Ketone Oxidoreductases; C097621:2-ketoisovalerate ferredoxin oxidoreductase