Enzymatic Synthesis of Dilactone Scaffold of Antimycins
Enzymatic Synthesis of Dilactone Scaffold of Antimycins
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DOI：
10.1021/cb300416w
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发表时间：
2012-12-01
影响因子：
4
通讯作者：
Zhang, Wenjun
中科院分区：
文献类型：
--
作者：
Sandy, Moriah;Rui, Zhe;Zhang, Wenjun
抗霉素类化合物是一类具有独特结构和生物活性的天然产物，半个多世纪来一直引起化学家的兴趣。抗霉素结构骨架建立在含有一个烷基、一个酰氧基、两个甲基部分和连接至3-甲酰氨基水杨酸的酰胺键的九元双内酯环上。虽然抗霉素的生物合成基因簇最近被确定，但控制抗霉素合成的酶逻辑尚未被揭示。在这项工作中，抗霉素的生物合成途径进行了解剖的遗传和酶学研究的第一次。确定了产生抗霉素双内酯支架所需的最小酶组，其特征在于含有顺式和反式作用组分的杂合非核糖体肽合成酶（NRPS）-聚酮化合物合成酶（PKS）装配线。几个抗霉素类似物进一步生产使用在体外酶促全合成的基础上，这种NRPS-PKS机制的底物混杂。
Antimycins are a family of natural products possessing outstanding biological activities and unique structures, which have intrigued chemists for over a half century. The antimycin structural skeleton is built on a nine-membered dilactone ring containing one alkyl, one acyloxy, two methyl moieties, and an amide linkage connecting to a 3-formamidosalicylic acid. Although a biosynthetic gene cluster for antimycins was recently identified, the enzymatic logic that governs the synthesis of antimycins has not yet been revealed. In this work, the biosynthetic pathway for antimycins was dissected by both genetic and enzymatic studies for the first time. A minimum set of enzymes needed for generation of the antimycin dilactone scaffold were identified, featuring a hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line containing both cis- and trans-acting components. Several antimycin analogues were further produced using in vitro enzymatic total synthesis based on the substrate promiscuity of this NRPS-PKS machinery.