title: Development of a Streptomyces venezuelae-based combinatorial biosynthetic system for the production of glycosylated derivatives of doxorubicin and its biosynthetic intermediates.
abstract: Doxorubicin, one of the most widely used anticancer drugs, is composed of a tetracyclic polyketide aglycone and l-daunosamine as a deoxysugar moiety, which acts as an important determinant of its biological activity. This is exemplified by the fewer side effects of semisynthetic epirubicin (4'-epi-doxorubicin). An efficient combinatorial biosynthetic system that can convert the exogenous aglycone ε-rhodomycinone into diverse glycosylated derivatives of doxorubicin or its biosynthetic intermediates, rhodomycin D and daunorubicin, was developed through the use of Streptomyces venezuelae mutants carrying plasmids that direct the biosynthesis of different nucleotide deoxysugars and their transfer onto aglycone, as well as the postglycosylation modifications. This system improved epirubicin production from ε-rhodomycinone by selecting a substrate flexible glycosyltransferase, AknS, which was able to transfer the unnatural sugar donors and a TDP-4-ketohexose reductase, AvrE, which efficiently supported the biosynthesis of TDP-4-epi-l-daunosamine. Furthermore, a range of doxorubicin analogs containing diverse deoxysugar moieties, seven of which are novel rhodomycin D derivatives, were generated. This provides new insights into the functions of deoxysugar biosynthetic enzymes and demonstrates the potential of the S. venezuelae-based combinatorial biosynthetic system as a simple biological tool for modifying structurally complex sugar moieties attached to anthracyclines as an alternative to chemical syntheses for improving anticancer agents.
authors: Interdisciplinary Programs of Bioengineering, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Ah Reum
authors: AR
authors: Han
authors: Je Won
authors: JW
authors: Park
authors: Mi Kyeong
authors: MK
authors: Lee
authors: Yeon Hee
authors: YH
authors: Ban
authors: Young Ji
authors: YJ
authors: Yoo
authors: Eun Ji
authors: EJ
authors: Kim
authors: Eunji
authors: E
authors: Kim
authors: Byung-Gee
authors: BG
authors: Kim
authors: Jae Kyung
authors: JK
authors: Sohng
authors: Yeo Joon
authors: YJ
authors: Yoon
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