Schwecke T, Aparicio J F, Molnár I, König A, Khaw L E, Haydock S F, Oliynyk M, Caffrey P, Cortés J, Lester J B
Department of Biochemistry, University of Cambridge, United Kingdom.
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7839-43. doi: 10.1073/pnas.92.17.7839.
The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis.
大环聚酮化合物雷帕霉素和FK506是强效免疫抑制剂，它们通过与细胞内蛋白质受体（亲免素）特异性结合来阻止T细胞增殖。对这些聚酮化合物生物合成基因的克隆和特异性改造可能会实现具有临床价值的类似物的生物合成。我们在此报告，吸水链霉菌中负责雷帕霉素生物合成的三个成簇聚酮合酶基因共同编码14套同源酶活性（模块），每个模块催化特定一轮的链延伸。一个相邻基因编码一种掺入哌啶酸的酶，该酶完成大环的合成。总共70个组成活性位点使其成为迄今为止鉴定出的最复杂的多酶系统。测序的DNA区域（107.3 kbp）包含另外24个开放阅读框，其中一些编码控制雷帕霉素生物合成中其他关键步骤的蛋白质。
