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Efficient Production of Anticancer Agent Cordycepin by Repeated Batch Culture of Cordyceps militaris Mutant

Cordycepin (3'-deoxyadenosine) exhibits antimicrobial, anticancer, antimetastatic, immunomodulatory and insecticidal effects, and is one of the most important bioactive anticancer agents found in Cordyceps species (summer grass-winter worm). However, due to the requirements of specific hosts and strict growth environments, Cordyceps militaris is very scarce in nature. Therefore, the production of the anticancer agent cordycepin from Cordyceps militaris in a large scale is currently an acute issue that might be solved by a repeated batch operation of surface liquid culture. In a course of searching a suitable culture technique, the repeated batch culture of control and, mutant with an optimized medium for each were used. The medium compositions were 62.6 g/l glucose, 72.5 g/l Yeast Extract (YE); and 86.2 glucose, 93.8 g/l YE for the control, and mutant, respectively. The cordycepin productivities (g/(l·d)) of batch and repeated batch were 0.16, 0.18, and 0.24, 0.44 for control, and mutant, respectively. Moreover, the productivity of the mutant in batch and repeated batch cultures were respectively increased to 0.26 g/(l·d) and 0.48 g/(l·d) by the addition of adenosine to the optimized medium. This is the highest cordycepin productivity (0.48 g/(l·d)) reported until now. In fact, the cordycepin productivities of the repeated batches were 34%, 86% and 82% higher than those of batches for control, mutant, and mutant with adenosine, respectively; whereas, those of mutant and mutant with adenosine were 113% and 131% higher than that of the control, respectively, indicating effectiveness of the repeated batch culture. The nucleic acid-related compounds analysis revealed that the major portion of cordycepin existed in the medium. Therefore, the Cordyceps militaris mutant (G81-3) obtained by a proton beam irradiation with the best additive concentration (adenosine 6 g/l) might be an effective combination for repeated batch culture in the optimized medium to achieve a further higher cordycepin productivity.