Cortes J, Haydock S F, Roberts G A, Bevitt D J, Leadlay P F
Department of Biochemistry, University of Cambridge, UK.
Nature. 1990 Nov 8;348(6297):176-8. doi: 10.1038/348176a0.
Erythromycin A, a clinically important polyketide antibiotic, is produced by the Gram-positive bacterium Saccharopolyspora erythraea. In an arrangement that seems to be generally true of antibiotic biosynthetic genes in Streptomyces and related bacteria like S. erythraea, the ery genes encoding the biosynthetic pathway to erythromycin are clustered around the gene (ermE) that confers self-resistance on S. erythraea. The aglycone core of erythromycin A is derived from one propionyl-CoA and six methylmalonyl-CoA units, which are incorporated head-to-tail into the growing polyketide chain, in a process similar to that of fatty-acid biosynthesis, to generate a macrolide intermediate, 6-deoxyerythronolide B. 6-Deoxyerythronolide B is converted into erythromycin A through the action of specific hydroxylases, glycosyltransferases and a methyltransferase. We report here the analysis of about 10 kilobases of DNA from S. erythraea, cloned by chromosome 'walking' outwards from the erythromycin-resistance determinant ermE, and previously shown to be essential for erythromycin biosynthesis. Partial sequencing of this region indicates that it encodes the synthase. Our results confirm this, and reveal a novel organization of the erythromycin-producing polyketide synthase, which provides further insight into the mechanism of chain assembly.
红霉素A是一种具有临床重要性的聚酮类抗生素，由革兰氏阳性菌糖多孢红霉菌产生。在链霉菌及相关细菌（如糖多孢红霉菌）中，抗生素生物合成基因的排列似乎通常如此，编码红霉素生物合成途径的ery基因聚集在赋予糖多孢红霉菌自身抗性的基因（ermE）周围。红霉素A的苷元核心源自一个丙酰辅酶A和六个甲基丙二酰辅酶A单元，它们以头对尾的方式掺入不断增长的聚酮链中，这一过程类似于脂肪酸生物合成，生成一个大环内酯中间体6-脱氧红霉内酯B。6-脱氧红霉内酯B通过特定羟化酶、糖基转移酶和甲基转移酶的作用转化为红霉素A。我们在此报告对来自糖多孢红霉菌约10千碱基DNA的分析，该DNA通过从红霉素抗性决定簇ermE向外进行染色体“步移”克隆得到，先前已证明其对红霉素生物合成至关重要。该区域的部分测序表明它编码合成酶。我们的结果证实了这一点，并揭示了产生红霉素的聚酮合酶的一种新组织方式，这为链组装机制提供了进一步的见解。
