Xue Y, Sherman D H
Department of Microbiology and Biological Process Technology Institute, University of Minnesota, Minneapolis 55455, USA.
Nature. 2000 Feb 3;403(6769):571-5. doi: 10.1038/35000624.
Modular polyketide synthases are giant multifunctional enzymes that catalyse the condensation of small carboxylic acids such as acetate and propionate into structurally diverse polyketides that possess a spectrum of biological activities. In a modular polyketide synthase, an enzymatic domain catalyses a specific reaction, and three to six enzymatic domains involved in a condensation-processing cycle are organized into a module. A fundamental aspect of a modular polyketide synthase is that its module arrangement linearly specifies the structure of its polyketide product. Here we report a natural example in which alternative expression of the pikromycin polyketide synthase results in the generation of two macrolactone structures. Expression of the full-length modular polyketide synthase PikAIV in Streptomyces venezuelae generates the 14-membered ring macrolactone narbonolide, whereas expression of the amino-terminal truncated form of PikAIV leads to 'skipping' of the final condensation cycle in polyketide biosynthesis to generate the 12-membered ring macrolactone 10-deoxymethynolide. Our findings provide insight into the structure and function of modular polyketide synthases, as well as a new set of tools to generate structural diversity in polyketide natural products.
模块聚酮合酶是一类巨大的多功能酶，可催化乙酸盐和丙酸盐等小分子羧酸缩合形成结构多样、具有一系列生物活性的聚酮化合物。在模块聚酮合酶中，一个酶结构域催化特定反应，参与缩合加工循环的三到六个酶结构域组成一个模块。模块聚酮合酶的一个基本特征是其模块排列线性地决定了其聚酮产物的结构。在此，我们报道了一个天然实例，其中苦霉素聚酮合酶的交替表达导致产生了两种大环内酯结构。全长模块聚酮合酶PikAIV在委内瑞拉链霉菌中表达产生14元环大环内酯纳波内酯，而PikAIV氨基末端截短形式的表达导致聚酮生物合成中最后一个缩合循环“跳过”，从而产生12元环大环内酯10-脱氧甲炔诺内酯。我们的发现为模块聚酮合酶的结构和功能提供了深入了解，同时也为在聚酮天然产物中产生结构多样性提供了一套新工具。
