Abstract
Chaetominine (CHA), an alkaloid with a biological activity obtained from Aspergillus fumigatus CY018, has strong anticancer activity against the human leukemia cells. However, its physiological and biochemical research is limited by CHA yield in the liquid-state fermentation, which is a problem that urgently needs effective biological solution. In this work, Ca2+ and Al3+ were found to have a strong promoting effect on CHA production after multiple metal ions screening. Then, the addition condition of Ca2+ and Al3+ was, respectively, optimized CHA production and dry cell weight. The intermediate metabolites were increased with coaddition of Ca2+ and Al3+ . The activities of key enzymes of DAHPs, AroAs, and TrpCs in the CHA biosynthesis pathway were improved by 3.58-, 3.60-, and 3.34-fold, respectively. Meanwhile, the transcription level of laeA, dahp, cs, and trpC was upregulated by 3.22-, 12.65-, 5.58-, and 6.99-fold, respectively, by coaddition of Ca2+ and Al3+ . Additionally, the fermentation strategy was successfully scaled up to a 5-L bioreactor, in which CHA production could attain 75.6 mg/L at 336 h. This work demonstrated that Ca2+ and Al3+ coaddition was an effective strategy for increasing CHA production, and the information obtained might be useful in the fermentation of filamentous fungi with the addition of metal ions.
Highlights
Aspergillus sp. as an endophytic fungus was excavated, and had received widespread attention by researchers in recent years [1]
Chaetominine (CHA), an alkaloid with biological activity produced by Aspergillus fumigatus CY018, has strong anticancer activity against the human leukemia cell
The activities of key enzymes of DAHP synthase (DAHPs), AroAs and TrpC synthase (TrpCs) in CHA biosynthesis pathway were improved by 3.58, 3.60- and 3.34-folds respectively
Summary
Aspergillus sp. as an endophytic fungus was excavated, and had received widespread attention by researchers in recent years [1]. Aspergillus fumigatus, an endophyte existing in plants, portunus and others, possessed an excellent synthesis ability of bioactive metabolites. The secondary metabolites biosynthesized by A. fumigatus had multiple biological activities. Fumigaclavine C, produced by A. fumigatus CY018 through the two-stage culture process, was an ergot alkaloid with anti-inflammatory activity [2]. Chaetominine (CHA) (Fig. S1) as a quinazolinone alkaloid from the endophytic fungi Aspergillus fumigatus CY018 was found to have greater cytotoxic activity than clinical drug, which implied CHA could be developed as an anti-cancer candidate [4,5,6]. The in-depth functional research and application of CHA had been seriously limited by the low production in the liquid fermentation. Further improvement of CHA production is urgently required considering its potential application in the field of medicine
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