Leadlay P F
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Curr Opin Chem Biol. 1997 Aug;1(2):162-8. doi: 10.1016/s1367-5931(97)80005-1.
Polyketides are a large and structurally diverse family of natural products based on chains of carboxylic acid units. The polyketide synthases that make aromatic polyketides have already been used to generate small combinatorial libraries, by expressing individual genes from different biosynthetic pathways together, so that the enzymes they encode can interact to make novel products. Recent work has shown how to choose these individual components to increase the chances of obtaining such hybrid aromatic compounds. In other polyketide synthases which synthesise complex reduced polyketides, the constituent enzymes are actually linked as domains in a giant multienzyme complex along which the growing polyketide chain is passed. A combinatorial approach here therefore requires the fusing together of individual enzymatic domains from several such synthases in as many productive ways as can be devised, so that the enzyme assembly line produces a library of altered products. A key recent advance has been to demonstrate that such genuinely hybrid enzymes do work as predicted, for example a broad-specificity enzyme that recruits the chain starter unit for an antiparasitic compound has been grafted onto a synthase that makes antimicrobial macrolides.
聚酮化合物是一类庞大且结构多样的天然产物家族，其基于羧酸单元链。用于合成芳香族聚酮化合物的聚酮合酶已被用于生成小型组合文库，方法是将来自不同生物合成途径的单个基因一起表达，这样它们编码的酶就能相互作用以产生新的产物。最近的研究表明了如何选择这些单个组分以增加获得此类杂合芳香族化合物的机会。在合成复杂还原型聚酮化合物的其他聚酮合酶中，组成酶实际上作为结构域连接在一个巨大的多酶复合物中，正在生长的聚酮链沿着该复合物传递。因此，这里的组合方法需要以尽可能多的有效方式将来自几种此类合酶的单个酶结构域融合在一起，以便酶装配线产生一个改变产物的文库。最近的一项关键进展是证明了这种真正的杂合酶确实如预期那样起作用，例如，一种招募抗寄生虫化合物链起始单元的广谱特异性酶已被嫁接到一种合成抗菌大环内酯的合酶上。
