Overexpression of aveBIV leading to the improvement of 4'-epidaunorubicin production in Streptomyces coeruleorubidus strain SIPI-A0707.
The 4'-epidaunorubicin is the semisynthesis precursor of epirubicin which is a clinically useful antitumor drug thought to have slightly less cardiotoxicity than doxorubin. The 4'-epidaunorubicin was formed by overexpression of heterologous Streptomyces avermitilis aveBIV in Streptomyces coeruleorubidus SIPI-A0707 dnmV mutant blocked in the biosynthesis of daunosamine, the deoxysugar component of daunorubicin. But there was a low-yield production of 4'-epidaunorubicin. In our study, product yields were enhanced considerably by increasing aveBIV gene copy number or changing means of aveBIV integration. The 4'-epidaunorubicin titer was improved by around threefold in the recombinant strain DYG1006 with the aveBIV increased threefold copy numbers. The transcript levels of aveBIV gene meet the expectation of fermentation levels of 4'-epidaunorubicin. The method described here provides the means to produce 4'-epidaunorubicin efficiently on an industrial scale.
Shao
Lei
L
State Key Lab of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai, 200040, China.
Huang
Jia
J
Jing
Lan
L
Chen
Ji-Ye
JY
Kan
Shi-Dong
SD
Wang
Min
M
Li
Ji-An
JA
Chen
Dai-Jie
DJ
D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*
D001426:Bacterial Proteins; C046084:3'-epidaunorubicin; D003630:Daunorubicin