Unusual carbon fixation gives rise to diverse polyketide extender units
Unusual carbon fixation gives rise to diverse polyketide extender units
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DOI：
10.1038/nchembio.734
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发表时间：
2012-01-01
影响因子：
14.8
通讯作者：
Mueller, Rolf
中科院分区：
文献类型：
--
作者：
Quade, Nick;Huo, Liujie;Mueller, Rolf
聚酮化合物是具有多种生物活性的结构多样且在医学上重要的天然产物。在生物合成过程中，链延长使用活化的二羧酸结构单元，因此它们的可用性限制了聚酮化合物中的侧链变化。最近，巴豆酰辅酶A羧化酶-还原酶（CCR）类的酶被确定在初级代谢中，并被发现参与聚酮化合物的延伸单元生物合成。理论上，这些酶能够形成显示来自相应不饱和脂肪酸前体的任何侧链的二羧酸。据我们所知，我们在这里报告的第一个晶体结构的CCR，己基丙二酰辅酶A合酶从链霉菌属JS 360，在复杂的与它的基板。的酶，包括活性位点突变的结构分析和生化特性的报告。我们的分析揭示了初级代谢CCR如何进化以产生各种二羧酸结构单元，从而为使用CCR生产独特的扩展单元并因此生产改变的聚酮化合物奠定了基础。
Polyketides are structurally diverse and medically important natural products that have various biological activities. During biosynthesis, chain elongation uses activated dicarboxylic acid building blocks, and their availability therefore limits side chain variation in polyketides. Recently, the crotonyl-CoA carboxylase-reductase (CCR) class of enzymes was identified in primary metabolism and was found to be involved in extender-unit biosynthesis of polyketides. These enzymes are, in theory, capable of forming dicarboxylic acids that show any side chain from the respective unsaturated fatty acid precursor. To our knowledge, we here report the first crystal structure of a CCR, the hexylmalonyl-CoA synthase from Streptomyces sp. JS360, in complex with its substrate. Structural analysis and biochemical characterization of the enzyme, including active site mutations, are reported. Our analysis reveals how primary metabolic CCRs can evolve to produce various dicarboxylic acid building blocks, setting the stage to use CCRs for the production of unique extender units and, consequently, altered polyketides.