Life Sciences Institute and Departments of Medicinal Chemistry, Microbiology, Immunology and Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI, USA.
Chembiochem. 2010 Mar 1;11(4):564-72. doi: 10.1002/cbic.200900658.
The structurally intriguing bicyclic ketal moiety of tirandamycin is common to several acyl-tetramic acid antibiotics, and is a key determinant of biological activity. We have identified the tirandamycin biosynthetic gene cluster from the environmental marine isolate Streptomyces sp. 307-9, thus providing the first genetic insight into the biosynthesis of this natural product scaffold. Sequence analysis revealed a hybrid polyketide synthase-nonribosomal peptide synthetase gene cluster with a colinear domain organization, which is entirely consistent with the core structure of the tirandamycins. We also identified genes within the cluster that encode candidate tailoring enzymes for elaboration and modification of the bicyclic ketal system. Disruption of tamI, which encodes a presumed cytochrome P450, led to a mutant strain deficient in production of late stage tirandamycins that instead accumulated tirandamycin C, an intermediate devoid of any post assembly-line oxidative modifications.
替拉菌素具有独特的双环缩酮结构，是几种酰基-四氢氨酸抗生素的共同结构，也是决定生物活性的关键因素。我们从海洋环境分离株链霉菌 sp. 307-9 中鉴定出替拉菌素生物合成基因簇，从而首次深入了解了该天然产物支架的生物合成。序列分析表明，该基因簇是一个具有线性结构域组织的混合聚酮合酶-非核糖体肽合成酶基因簇，与替拉霉素的核心结构完全一致。我们还在该基因簇中鉴定出了一些基因，这些基因编码候选的修饰酶，用于双环缩酮系统的衍生和修饰。tamI 基因编码一个假定的细胞色素 P450，阻断该基因会导致晚期替拉霉素产生缺陷的突变株，而替拉霉素 C 积累，替拉霉素 C 是一种没有任何后期组装线氧化修饰的中间体。
