Nguyen TuAnh, Ishida Keishi, Jenke-Kodama Holger, Dittmann Elke, Gurgui Cristian, Hochmuth Thomas, Taudien Stefan, Platzer Matthias, Hertweck Christian, Piel Jörn
Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany.
Nat Biotechnol. 2008 Feb;26(2):225-33. doi: 10.1038/nbt1379. Epub 2008 Jan 27.
Modular polyketide synthases (PKSs) are giant bacterial enzymes that synthesize many polyketides of therapeutic value. In contrast to PKSs that provide acyltransferase (AT) activities in cis, trans-AT PKSs lack integrated AT domains and exhibit unusual enzymatic features with poorly understood functions in polyketide assembly. This has retarded insight into the assembly of products such as mupirocin, leinamycin and bryostatin 1. We show that trans-AT PKSs evolved in a fundamentally different fashion from cis-AT systems, through horizontal recruitment and assembly of substrate-specific ketosynthase (KS) domains. The insights obtained from analysis of these KS mosaics will facilitate both the discovery of novel polyketides by genome mining, as we demonstrate for the thailandamides of Burkholderia thailandensis, and the extraction of chemical information from short trans-AT PCR products, as we show using metagenomic DNA of marine sponges. Our data also suggest new strategies for dissecting polyketide biosynthetic pathways and engineering polyketide assembly.
模块化聚酮合酶（PKSs）是一类巨大的细菌酶，可合成许多具有治疗价值的聚酮化合物。与顺式提供酰基转移酶（AT）活性的PKSs不同，反式AT PKSs缺乏整合的AT结构域，并表现出不寻常的酶学特征，在聚酮化合物组装中的功能了解甚少。这阻碍了对诸如莫匹罗星、连霉素和苔藓抑素1等产物组装的深入了解。我们发现，反式AT PKSs与顺式AT系统在根本上以不同的方式进化，是通过水平募集和组装底物特异性酮合成酶（KS）结构域实现的。通过对这些KS镶嵌体的分析获得的见解，将有助于通过基因组挖掘发现新型聚酮化合物，正如我们对泰国伯克霍尔德菌的泰国酰胺所展示的那样，也有助于从短的反式AT PCR产物中提取化学信息，正如我们使用海洋海绵宏基因组DNA所展示的那样。我们的数据还为剖析聚酮化合物生物合成途径和工程化聚酮化合物组装提出了新策略。
