Van Lanen Steven G, Shen Ben
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536, USA.
Curr Opin Drug Discov Devel. 2008 Mar;11(2):186-95.
Recent progress in the understanding of polyketide synthase (PKS) continues to fuel the growth of combinatorial biosynthesis for natural product structural diversity. The structural analysis of many components of PKS, in particular for the modular type I 6-deoxyerythronilide B synthase (DEBS) involved in erythromycin biosynthesis, has provided structural imperatives for the observed biochemistry of DEBS and has enabled the generation of a working structural model of the entire DEBS system. New functions for PKS domains continue to be defined, such as the general control nonderepressible 5 (GCN5) N-acyltransferase strategy for polyketide chain initiation and the true identity of the elusive precursor for the methoxymalonylate extender unit. Novel molecular architectures have been continuously uncovered, including the 'AT-less' PKS and enediyne PKS, thereby expanding the known bacterial PKS paradigms beyond the prototypical type I, II and III PKSs. Finally, the genetic characterization of PKS in vivo and biochemical studies of PKS in vitro have also been greatly facilitated by the application of emerging technologies, such as RNA-mediated gene silencing, reconstitution of an entire polyketide biosynthetic pathway in a model heterologous host and Fourier-transform mass spectroscopy. The application of these technologies is discussed.
在聚酮合酶（PKS）理解方面的最新进展持续推动着用于天然产物结构多样性的组合生物合成的发展。对PKS许多组分的结构分析，特别是对参与红霉素生物合成的模块化I型6 - 脱氧红霉内酯B合酶（DEBS）的结构分析，为观察到的DEBS生物化学提供了结构依据，并使得能够构建整个DEBS系统的有效结构模型。PKS结构域的新功能不断被定义，例如用于聚酮链起始的一般控制非抑制性5（GCN5）N - 酰基转移酶策略以及甲氧基丙二酸酯延伸单元难以捉摸的前体的真实身份。新型分子结构不断被发现，包括“无AT”PKS和烯二炔PKS，从而将已知的细菌PKS模式扩展到原型I型、II型和III型PKS之外。最后，新兴技术的应用，如RNA介导的基因沉默、在模型异源宿主中重建整个聚酮生物合成途径以及傅里叶变换质谱，也极大地促进了PKS在体内的遗传表征和在体外的生化研究。本文讨论了这些技术的应用。
