Enhanced production of ansamitocin P-3 by addition of isobutanol in fermentation of Actinosynnema pretiosum

Abstract

Supply of isobutanol to enhance the production of anti-tumor agent ansamitocin P-3 (AP-3) in medium containing agro-industrial residues was investigated with analysis of gene transcription, enzyme activity, and intermediate accumulation. Under the optimal addition of isobutanol, about 4-fold improvement of AP-3 production was obtained, and the consumption of isobutanol and accumulation of isobutyrate, malonyl-CoA, and acetyl-CoA were observed. Compared to the control without isobutanol addition, activities of both isobutanol dehydrogenase and valine dehydrogenase were enhanced in isobutanol supplemented culture. Transcription level of genes in AP-3 biosynthetic and isobutyryl-CoA catabolic pathways responded to isobutanol addition in a similar way as AP-3 biosynthesis. It is concluded that isobutanol addition was an effective strategy for increasing AP-3 production via regulation of gene transcription and pools of precursors, and the information obtained might be helpful to the fermentation productivity improvement on large scale.