ENGINEERED BIOSYNTHESIS OF NOVEL POLYKETIDES
ENGINEERED BIOSYNTHESIS OF NOVEL POLYKETIDES
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DOI：
10.1126/science.8248802
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发表时间：
1993-12-03
期刊：
影响因子：
56.9
通讯作者：
KHOSLA, C
中科院分区：
文献类型：
--
作者：
MCDANIEL, R;EBERTKHOSLA, S;KHOSLA, C
聚酮酶（PKS）是多功能酶，其催化在其长度和功能性和环化模式上不同的大量碳链的生物合成。许多聚酮化合物是有价值的治疗剂。链霉菌宿主载体系统已被开发用于高效构建和表达重组PKS。使用这种表达系统，已经在体内大量合成了几种新的化合物。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，碳链长度至少部分取决于PKS家族特有的蛋白质，而不同PKS的酰基载体蛋白可以互换而不影响产物结构。给定的酮还原酶可以识别并还原不同长度的聚酮化合物链;这种酮还原总是发生在C-9位置。新生聚酮化合物链的第一次环化的区域特异性由酮还原酶或扩链酶本身决定。然而，第二环化的区域特异性由不同的环化酶决定，其可以区分不同链长的底物。
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.