Development of a Streptomyces venezuelae-Based Combinatorial Biosynthetic System for the Production of Glycosylated Derivatives of Doxorubicin and Its Biosynthetic Intermediates
Development of a Streptomyces venezuelae-Based Combinatorial Biosynthetic System for the Production of Glycosylated Derivatives of Doxorubicin and Its Biosynthetic Intermediates
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DOI：
10.1128/aem.02527-10
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发表时间：
2011-07-01
影响因子：
4.4
通讯作者：
Yoon, Yeo Joon
中科院分区：
文献类型：
--
作者：
Han, Ah Reum;Park, Je Won;Yoon, Yeo Joon
多柔比星是目前应用最广泛的抗肿瘤药物之一，由四环聚酮苷元和脱氧糖基L-柔红霉素胺组成，后者是其生物活性的重要决定因素。这通过半合成表阿霉素（4 '-表阿霉素）的较少副作用来例证。一种有效的组合生物合成系统，可以将外源糖苷配基ε-玫瑰霉素酮转化为多柔比星的各种糖基化衍生物或其生物合成中间体，玫瑰霉素D和柔红霉素，开发通过使用委内瑞拉链霉菌突变体携带质粒，该质粒指导不同核苷酸脱氧糖的生物合成及其转移到糖苷配基上，以及糖基化后修饰。该系统通过选择能够转移非天然糖供体的底物柔性糖基转移酶AknS和有效支持TDP-4-表-L-道诺糖胺生物合成的TDP-4-己酮糖还原酶AvrE来改善从ε-玫瑰霉素酮的表阿霉素生产。此外，生成了一系列含有不同脱氧糖部分的多柔比星类似物，其中七个是新的罗多霉素D衍生物。这为脱氧糖生物合成酶的功能提供了新的见解，并展示了S。基于委内瑞拉的组合生物合成系统作为一种简单的生物学工具，用于修饰与蒽环类药物连接的结构复杂的糖部分，作为改进抗癌剂的化学合成的替代方案。
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.