McDaniel R, Ebert-Khosla S, Hopwood D A, Khosla C
Department of Chemical Engineering, Stanford University, CA 94305-5025.
Science. 1993 Dec 3;262(5139):1546-50. doi: 10.1126/science.8248802.
Polyketide synthases (PKSs) are multifunctional enzymes that catalyze the biosynthesis of a huge variety of carbon chains differing in their length and patterns of functionality and cyclization. Many polyketides are valuable therapeutic agents. A Streptomyces host-vector system has been developed for efficient construction and expression of recombinant PKSs. Using this expression system, several novel compounds have been synthesized in vivo in significant quantities. Characterization of these metabolites has provided new insights into key features of actinomycete aromatic PKS specificity. Thus, carbon chain length is dictated, at least in part, by a protein that appears to be distinctive to this family of PKSs, whereas the acyl carrier proteins of different PKSs can be interchanged without affecting product structure. A given ketoreductase can recognize and reduce polyketide chains of different length; this ketoreduction always occurs at the C-9 position. The regiospecificity of the first cyclization of the nascent polyketide chain is either determined by the ketoreductase, or the chain-extending enzymes themselves. However, the regiospecificity of the second cyclization is determined by a distinct cyclase, which can discriminate between substrates of different chain lengths.
聚酮合酶（PKSs）是多功能酶，可催化生物合成种类繁多、长度、官能团模式和环化方式各异的碳链。许多聚酮化合物都是有价值的治疗剂。已开发出一种用于高效构建和表达重组PKSs的链霉菌宿主-载体系统。利用该表达系统，已在体内大量合成了几种新型化合物。对这些代谢产物的表征为放线菌芳香族PKS特异性的关键特征提供了新的见解。因此，碳链长度至少部分由一种似乎是该PKS家族特有的蛋白质决定，而不同PKS的酰基载体蛋白可以互换而不影响产物结构。特定的酮还原酶可以识别并还原不同长度的聚酮链；这种酮还原总是发生在C-9位。新生聚酮链第一次环化的区域特异性要么由酮还原酶决定，要么由链延伸酶本身决定。然而，第二次环化的区域特异性由一种独特的环化酶决定，该环化酶可以区分不同链长的底物。
