Open AccessDevelopment of a Streptomyces venezuelae-Based Combinatorial Biosynthetic System for the Production of Glycosylated Derivatives of Doxorubicin and Its Biosynthetic Intermediates
Author(s) -
Ah Reum Han,
Je Won Park,
Mi Kyeong Lee,
Yeon Hee Ban,
Young Je Yoo,
Young Ho Kim,
Eunji J. Kim,
ByungGee Kim,
Jae Kyung Sohng,
Yeo Joon Yoon
Publication year - 2011
Publication title -
applied and environmental microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.552
H-Index - 324
eISSN - 1070-6291
pISSN - 0099-2240
DOI - 10.1128/aem.02527-10
Subject(s) - aglycone , polyketide , biosynthesis , glycosyltransferase , daunorubicin , biochemistry , streptomyces , chemistry , doxorubicin , stereochemistry , enzyme , biology , glycoside , bacteria , chemotherapy , leukemia , genetics
Doxorubicin, one of the most widely used anticancer drugs, is composed of a tetracyclic polyketide aglycone andl -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 ofStreptomyces 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 theS. 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.