Zhang Jian, Van Lanen Steven G, Ju Jianhua, Liu Wen, Dorrestein Pieter C, Li Wenli, Kelleher Neil L, Shen Ben
Department of Chemistry, Division of Pharmaceutical Sciences, and University of Wisconsin National Cooperative Drug Discovery Group, University of Wisconsin, Madison, WI 53705, USA.
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1460-5. doi: 10.1073/pnas.0711625105. Epub 2008 Jan 25.
The enediynes, unified by their unique molecular architecture and mode of action, represent some of the most potent anticancer drugs ever discovered. The biosynthesis of the enediyne core has been predicted to be initiated by a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization of the enediyne PKS involved in C-1027 (SgcE) and neocarzinostatin (NcsE) biosynthesis has now revealed that (i) the PKSs contain a central acyl carrier protein domain and C-terminal phosphopantetheinyl transferase domain; (ii) the PKSs are functional in heterologous hosts, and coexpression with an enediyne thioesterase gene produces the first isolable compound, 1,3,5,7,9,11,13-pentadecaheptaene, in enediyne core biosynthesis; and (iii) the findings for SgcE and NcsE are likely shared among all nine-membered enediynes, thereby supporting a common mechanism to initiate enediyne biosynthesis.
烯二炔类化合物因其独特的分子结构和作用方式而具有一致性，是迄今发现的一些最有效的抗癌药物。烯二炔核心的生物合成预计由一种与所有已知聚酮合酶（PKS）不同的聚酮合酶启动。参与C-1027（SgcE）和新制癌菌素（NcsE）生物合成的烯二炔PKS的表征现已表明：（i）这些PKS含有一个中央酰基载体蛋白结构域和C端磷酸泛酰巯基乙胺基转移酶结构域；（ii）这些PKS在异源宿主中具有功能，并且与烯二炔硫酯酶基因共表达可产生烯二炔核心生物合成中的首个可分离化合物1,3,5,7,9,11,13-十五碳七烯；（iii）SgcE和NcsE的研究结果可能在所有九元烯二炔中都存在，从而支持烯二炔生物合成起始的共同机制。
