Insights into Quinaldic Acid Moiety Formation in Thiostrepton Biosynthesis Facilitating Fluorinated Thiopeptide Generation
Insights into Quinaldic Acid Moiety Formation in Thiostrepton Biosynthesis Facilitating Fluorinated Thiopeptide Generation
复制标题
深入了解硫链丝菌素生物合成中喹哪二酸部分的形成，促进氟化硫肽的生成
DOI：
10.1016/j.chembiol.2012.02.008
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发表时间：
2012-04-20
影响因子：
--
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Duan, Lian;Wang, Shoufeng;Liu, Wen
硫链丝菌肽（TSR），通常被称为硫肽家族中的母体化合物，是一种双大环成员，其特征在于含有喹哪酸（QA）部分的侧环附加到特征核心系统。QA的生物合成需要一个不寻常的扩环转化，显示甲基转移到L-色氨酸的吲哚部分，并重排，得到喹啉酮。在此，我们报告，该过程涉及的自由基甲基转移酶TsrT，转氨酶TsrA，脱氢酶TsrE，和环化酶TsrD的活动。TsrU是一种立体特异性氧化还原酶，催化酮进一步转化为对映体纯的S-醇。这种化学的阐明，这是常见的生物合成的硫肽共享QA侧环系统，促进类似物的产生，如所示的实现具有改善的抗菌活性的硫链丝菌素的区域特异性的双链。
Thiostrepton (TSR), often referred as to a parent compound in the thiopeptide family, is a bimacrocyclic member that features a quinaldic acid (QA) moiety-containing side ring appended to the characteristic core system. QA biosynthesis requires an unusual ring-expanding conversion, showing a methyl transfer onto and a rearrangement of the indole part of L-tryptophan to give a quinoline ketone. Herein, we report that the process involves the activities of the radical methyltransferase TsrT, aminotransferase TsrA, dehydrogenase TsrE, and cyclase TsrD. TsrU, a stereospecific oxidoreductase, catalyzes the further conversion of the ketone into an enantiomerically pure S-alcohol. Elucidation of this chemistry, which is common in the biosynthesis of a number of thiopeptides sharing a QA side ring system, facilitates analog generation, as shown by the achievement of region-specific fluorination of thiostrepton with the improved antibacterial activity.