Enhanced Production Of Ansamistocin P-3 By Addition Of Mg²⁺ In Fermentation Of Actinosynnema Pretiosum

Ansamitocins are potent antitumor maytansinoids produced by Actinosynnema pretiosum; therein ansamitocin P-3 (AP-3) presented excellent activity. Although AP-3 beared outstanding physiological activity and its biosynthetic pathways have been released, its production was still low, and seldom research focused on its fermentation process In this study, effect of divalent metal ions (Mn2+, Mg2+, Zn2+, Cu2+, and Co2+) on production of anticancer ansamitocin P-3 (AP-3) by submerged cultures of Actinosynnema pretiosum was investigated, and magnesium ion was found the most effective. Under an optimal Mg2+ addition, maximal AP-3 production was 85 mg/L, which was 3.0-folds that of the control. Meanwhile, the activities of methylmalonyl-CoA carboxyltransferase and methylmalonyl-CoA mutase were enhanced, and the content of two precursors, malonyl-CoA and methylmalonyl-CoA, were lower than the control. Transcription levels of structure genes asm14, asm24 and asm43, and regulatory genes asm39 and asm40 were up-regulated while that of asm8 was slightly down-regulated by Mg2+. This study demonstrated that Mg2+ addition was a simple and effective strategy for increasing AP-3 production via regulation of gene transcription and pools of precursors, and the information obtained might be helpful to its production improvement on a large scale.