Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus.
The production of C-1027 in Streptomyces globisporus was previously increased 2- to 3-fold by manipulating three pathway-specific activators, SgcR1, SgcR2, and SgcR3. In this study, we have further characterized two putative C-1027 regulatory genes, sgcE1 and sgcR, by in vivo inactivation. The HxlR family DNA-binding protein SgcE1 was not essential for C-1027 biosynthesis, since inactivation of sgcE1 showed no effect on C-1027 production. In contrast, the proposed repressive role of the sgcR gene was confirmed by a 3-fold increase in C-1027 production in the ΔsgcR mutant S. globisporus SB1022 strain relative to the wild-type strain. Considering SgcR shows no significant similarity to any protein of known function, it may be representative of a new family of regulatory proteins. Finally, overexpression of the previously characterized activator sgcR1 in S. globisporus SB1022 increased the C-1027 yield to 37.5 ± 7.7 mg/L, which is about 7-fold higher than the wild-type strain.
Division of Pharmaceutical Sciences, University of Wisconsin-Madison , Madison, Wisconsin 53705-2222, United States.
Yihua
Y
Chen
Min
M
Yin
Geoff P
GP
Horsman
Ben
B
Shen
D000617:Aminoglycosides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001483:Base Sequence; D053898:Biosynthetic Pathways / Q000235:genetics; D053281:Enediynes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial; D015394:Molecular Structure; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; C058024:C 1027
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