期刊
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
卷 77, 期 14, 页码 4912-4923出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AEM.02527-10
关键词
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资金
- Nation Research Foundation of Korea (NRF) [20100018430]
- Ministry of Education, Science, and Technology [2010K000890, 20100001487]
- Ministry of Land, Transportation and Maritime Affairs, Republic of Korea [0620029]
- Korea Health Promotion Institute [0620290] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Korea Institute of Marine Science & Technology Promotion (KIMST) [20046001] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2008-0059999, 2008-0057903] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 epsilon-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 epsilon-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.
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