Donadio S, Sosio M
Vicuron Pharmaceuticals, Gerenzano, Italy.
Comb Chem High Throughput Screen. 2003 Sep;6(6):489-500. doi: 10.2174/138620703106298671.
Polyketides are assembled by the polyketide synthases (PKS) through a common mechanism, the condensation of small carboxylic acids. However, a large structural variety exists within these molecules, paralleled by their different bioactivities. Structural differences in polyketides mostly stem from variations in the number of elongation cycles, in the extender unit incorporated and the extent of processing occurring during each cycle. A significant fraction of polyketides is made in bacteria by modular PKSs, which direct polyketide synthesis on a protein template, where each module is responsible for selecting, incorporating and processing the appropriate carboxylate unit. Since their discovery in the early nineties, the architecture of modular PKSs and their modus operandi have attracted efforts by several laboratories to reprogram PKSs to produce tailor-made polyketides. The availability of a growing number of modular PKSs of defined sequence, and of well-developed model systems for the in vitro and in vivo analysis of these enzymes, has led to the successful production of many novel polyketides after genetic manipulation of the appropriate PKS. We discuss the different strategies that are followed for the construction of functional "hybrid" systems, with particular emphasis on what can be done in terms of generating chemical diversity, highlighting also the limitations of our current understanding. The prospects of generating novel useful polyketides by genetic engineering are also discussed.
聚酮化合物由聚酮合酶（PKS）通过一种常见机制——小羧酸的缩合反应进行组装。然而，这些分子具有很大的结构多样性，同时伴有不同的生物活性。聚酮化合物的结构差异主要源于延伸循环次数、掺入的延伸单元以及每个循环中发生的加工程度的变化。很大一部分聚酮化合物是由模块化PKS在细菌中合成的，这些模块化PKS在蛋白质模板上指导聚酮化合物的合成，其中每个模块负责选择、掺入和加工合适的羧酸盐单元。自20世纪90年代初被发现以来，模块化PKS的结构及其作用方式吸引了多个实验室努力对PKS进行重新编程，以生产定制的聚酮化合物。越来越多具有明确序列的模块化PKS以及用于这些酶体外和体内分析的完善模型系统的出现，使得在对合适的PKS进行基因操作后成功生产出许多新型聚酮化合物。我们讨论了构建功能性“杂交”系统所采用的不同策略，特别强调在产生化学多样性方面可以做些什么，同时也突出了我们目前理解的局限性。还讨论了通过基因工程产生新型有用聚酮化合物的前景。
