MacNeil D J, Occi J L, Gewain K M, MacNeil T
Department of Microbial Chemotherapeutics and Molecular Genetics, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065.
Ann N Y Acad Sci. 1994 May 2;721:123-32. doi: 10.1111/j.1749-6632.1994.tb47384.x.
Streptomyces avermitilis produces a series of eight potent anthelmintic compounds called avermectins (AVM). AVM are pentacyclic, macrocyclic lactone compounds containing an oleandrose disaccharide. Labeling studies have shown that AVM is a polyketide derived from the condensation of 12 acyl units (five propionates and seven acetates) to an isobutyl or 2-methylbutyryl starter unit. The genes required for AVM biosynthesis have been cloned, and deletion mapping has located the AVM gene cluster to a 95-kb region. Partial DNA sequencing of this region indicates two 30-kb segments encode large, multifunctional peptides of the AVM polyketide synthase (PKS). The PKS proteins contain at least 49 domains with homology to the domains in fatty acid synthase and erythromycin PKS. These domains are arranged as 12 modular repeats that each encode a PKS unit with various subsets of the FAS-like functions. The predicted functions required to form the side groups on the AVM macrocyclic ring were compared to the functions found in the 12 PKS units. This comparison suggests that each PKS unit is specific for condensation and reduction of one acyl unit. If the various domains can be manipulated without disrupting the PKS, it may be possible to synthesize a variety of AVM derivatives.
阿维链霉菌产生一系列八种强效驱虫化合物，称为阿维菌素（AVM）。AVM是含有夹竹桃二糖的五环大环内酯化合物。标记研究表明，AVM是一种聚酮化合物，由12个酰基单元（五个丙酸酯和七个乙酸酯）缩合到异丁基或2-甲基丁酰起始单元上形成。AVM生物合成所需的基因已被克隆，缺失定位已将AVM基因簇定位到一个95 kb的区域。该区域的部分DNA测序表明，两个30 kb的片段编码AVM聚酮合酶（PKS）的大型多功能肽。PKS蛋白包含至少49个与脂肪酸合酶和红霉素PKS中的结构域具有同源性的结构域。这些结构域排列成12个模块化重复序列，每个重复序列编码一个具有各种类似脂肪酸合酶功能子集的PKS单元。将形成AVM大环环上侧链所需的预测功能与12个PKS单元中发现的功能进行了比较。这种比较表明，每个PKS单元对一个酰基单元的缩合和还原具有特异性。如果在不破坏PKS的情况下可以操纵各种结构域，则有可能合成多种AVM衍生物。
