AN ERYTHROMYCIN ANALOG PRODUCED BY REPROGRAMMING OF POLYKETIDE SYNTHESIS
AN ERYTHROMYCIN ANALOG PRODUCED BY REPROGRAMMING OF POLYKETIDE SYNTHESIS
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DOI：
10.1073/pnas.90.15.7119
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发表时间：
1993-08-01
影响因子：
11.1
通讯作者：
KATZ, L
中科院分区：
文献类型：
--
作者：
DONADIO, S;MCALPINE, JB;KATZ, L
抗生素红霉素的聚酮基大内酯是由七个三碳单元连续缩合和加工而成的。第四个循环包括对新形成的β-酮基(β-酮基还原、脱水和烯基还原)进行完全处理，以生成内酯环的C-7位上的亚甲基。该分子在糖多孢菌中的合成由三个大的erA基因决定，这些基因由六个模块组成，每个模块控制一个缩合循环。在由eryAII编码的Enoyl还原酶结构域的NAD(P)H结合基序中引入了两个氨基酸取代。该菌株产生的代谢物经鉴定为DELTA6，7-苯氧红霉素C，这是由于在大内酯合成的第四个周期中烯醇基还原失败所致。这一结果表明，在第四个周期中，至少有第四个模块的烯醇还原酶参与，并表明通过重新编程聚酮合成可以产生几乎完整的大环内酯类化合物。
The polyketide-derived macrolactone of the antibiotic erythromycin is made through successive condensation and processing of seven three-carbon units. The fourth cycle involves complete processing of the newly formed beta-keto group (beta-keto reduction, dehydration, and enoyl reduction) to yield the methylene that will appear at C-7 of the lactone ring. Synthesis of this molecule in Saccharopolyspora erythraea is determined by the three large eryA genes, organized in six modules, each governing one condensation cycle. Two amino acid substitutions were introduced in the putative NAD(P)H binding motif in the proposed enoyl reductase domain encoded by eryAII. The metabolite produced by the resulting strain was identified as DELTA6,7-anbydroerythromycin C resulting from failure of enoyl reduction during the fourth cycle of synthesis of the macrolactone. This result demonstrates the involvement of at least the enoyl reductase from the fourth module in the fourth cycle and indicates that a virtually complete macrolide can be produced through reprogramming of polyketide synthesis.