Biosynthetic origins of the natural product, thiolactomycin: A unique and selective inhibitor of type II dissociated fatty acid synthases
Biosynthetic origins of the natural product, thiolactomycin: A unique and selective inhibitor of type II dissociated fatty acid synthases
复制标题
DOI：
10.1021/ja034540i
复制
发表时间：
2003-08-27
影响因子：
15
通讯作者：
Reynolds, KA
中科院分区：
文献类型：
--
作者：
Brown, MS;Akopiants, K;Reynolds, KA
硫拉霉素（TLM）是诺卡菌属和链霉菌属的天然产物。是植物和细菌II型游离脂肪酸合成酶的有效和高选择性抑制剂。TLM独特的作用方式和低毒性使其成为开发新型抗菌药物的有吸引力的化合物。在这项研究中，与13c标记前体的结合研究表明，TLM是由一个醋酸酯衍生的起始单元和三个甲基丙二酸衍生的扩展单元衍生的。TLM所代表的不寻常的硫内酯代表了一类新的聚酮衍生抗生素，其中不寻常的环化过程终止了生物合成途径，涉及l-半胱氨酸硫原子的掺入。通过组合生物合成和突变合成等技术来操纵这一途径可能为经济上可行的生产有用的TLM类似物提供新的途径。
Thiolactomycin (TLM), a natural product produced by bothNocardiaandStreptomycesspp., is a potent and highly selective inhibitor of the type II dissociated fatty acid synthases of plants and bacteria. The unique mode of action of TLM and its low toxicity make it an attractive compound for development of new antimicrobial agents. In this study, incorporation studies with13C-labeled precursors demonstrate that TLM is derived from one acetate-derived starter unit and three methylmalonate-derived extender units. The unusual thiolactone represented by TLM represents a novel class of polyketide-derived antibiotics in which an unusual cyclization process, which terminates the biosynthetic pathway, involves incorporation of a sulfur atom froml-cysteine. Manipulation of this pathway through techniques such a combinatorial biosynthesis and mutasynthesis may provide a new route for economically viable production of useful TLM analogues.