Induced effect of Ca2+ and Al3+ on chaetominine synthesis by Aspergillus fumigatus CY018 under submerged fermentation

Chaetominine (CHA), an alkaloid with biological activity produced by Aspergillus fumigatus CY018, has strong anticancer activity against the human leukemia cell. However, its further research for pharmacokinetics is limited by CHA production in submerged fermentation, which is a problem urgently awaiting solutions by effective biological strategies. In this work, Ca2+ and Al3+ exhibited a strong promoting effect on CHA production after multiple metal ions screening. Then, the concentration of Ca2+ and Al3+ and the addition time was optimized. The suitable conditions were 0.5 mM Ca2+ and 0.5 mM Al3+ at 120 h, in which the CHA production reached 58.5 and 49.45 mg/L with optimized condition of Ca2+ and Al3+ respectively. The intermediate metabolites, such as DAHP, chorismate and tryptophan, were increased obviously with addition of Ca2+ and Al3+. The activities of key enzymes of DAHPs, AroAs and TrpCs in CHA biosynthesis pathway were improved by 3.58-, 3.60- and 3.34-folds respectively. Meanwhile, the transcription levels of laeA, dahp, cs, and trpC were upregulated by 3.22-, 12.65-, 5.58- and 6.99-fold respectively by addition of Ca2+ and Al3+. Additionally, the fermentation strategy was successfully scaled up to 5 L reactor, in which CHA production could attain 75.6 mg/L at 336 h. This work demonstrated that Ca2+ and Al3+ co-addition was an effective strategy for increasing CHA production, and the information obtained might be useful to the further improvement of CHA fermentation on large scale.