Jacobsen J R, Hutchinson C R, Cane D E, Khosla C
Department of Chemical Engineering, Stanford University, Stanford, CA 94305-5025, USA.
Science. 1997 Jul 18;277(5324):367-9. doi: 10.1126/science.277.5324.367.
A genetic block was introduced in the first condensation step of the polyketide biosynthetic pathway that leads to the formation of 6-deoxyerythronolide B (6-dEB), the macrocyclic precursor of erythromycin. Exogenous addition of designed synthetic molecules to small-scale cultures of this null mutant resulted in highly selective multimilligram production of unnatural polyketides, including aromatic and ring-expanded variants of 6-dEB. Unexpected incorporation patterns were observed, illustrating the catalytic versatility of modular polyketide synthases. Further processing of some of these scaffolds by postpolyketide enzymes of the erythromycin pathway resulted in the generation of novel antibacterials with in vitro potency comparable to that of their natural counterparts.
在聚酮生物合成途径的第一步缩合反应中引入了一个基因阻断，该途径导致红霉素的大环前体6-脱氧红霉内酯B（6-dEB）的形成。向该基因敲除突变体的小规模培养物中外源添加设计的合成分子，可高度选择性地多毫克生产非天然聚酮化合物，包括6-dEB的芳香族和环扩展变体。观察到了意外的掺入模式，说明了模块化聚酮合酶的催化多功能性。红霉素途径的聚酮后修饰酶对其中一些支架的进一步加工，产生了体外效力与其天然对应物相当的新型抗菌剂。
