Department of Chemistry, University of Warwick, Coventry, UK.
1] Université de Lorraine, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France [2] INRA, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France.
J Antibiot (Tokyo). 2014 Jan;67(1):71-6. doi: 10.1038/ja.2013.119. Epub 2013 Nov 13.
Many polyketide antibiotics contain macrolactones that arise from polyketide synthase chain release via thioesterase (TE) domain-catalyzed macrolactonization. The hydroxyl groups utilized in such macrolactonization reactions typically derive from reduction of β-ketothioester intermediates in polyketide chain assembly. The stambomycins are a group of novel macrolide antibiotics with promising anticancer activity that we recently discovered via rational activation of a silent polyketide biosynthetic gene cluster in Streptomyces ambofaciens. Here we report that the hydroxyl group utilized for formation of the macrolactone in the stambomycins is derived from cytochrome P450-catalyzed hydroxylation of the polyketide chain rather than keto reduction during chain assembly. This is a novel mechanism for macrolactone formation in polyketide antibiotic biosynthesis.
许多聚酮类抗生素含有大环内酯，它们通过硫酯酶（TE）结构域催化的大环内酯化作用从聚酮合酶链释放。此类大环内酯化反应中使用的羟基通常来源于聚酮链组装过程中β-酮硫酯中间体的还原。Stambomycins 是一组新型大环内酯类抗生素，具有有前景的抗癌活性，我们最近通过理性激活链霉菌属中沉默的聚酮生物合成基因簇发现了它们。在这里，我们报告说，Stambomycins 中环内酯形成所使用的羟基来自细胞色素 P450 催化的聚酮链羟化，而不是链组装过程中的酮还原。这是聚酮类抗生素生物合成中环内酯形成的一种新机制。
