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Structural and Functional Studies of the Daunorubicin Priming Ketosynthase DpsC
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acschembio.7b00551 David R. Jackson 1 , Gaurav Shakya 1 , Avinash B. Patel 1 , Lina Y. Mohammed 2 , Kostas Vasilakis 2 , Pakorn Wattana-Amorn 2 , Timothy R. Valentic 1 , Jacob C. Milligan 1 , Matthew P. Crump 2 , John Crosby 2 , Shiou-Chuan Tsai 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acschembio.7b00551 David R. Jackson 1 , Gaurav Shakya 1 , Avinash B. Patel 1 , Lina Y. Mohammed 2 , Kostas Vasilakis 2 , Pakorn Wattana-Amorn 2 , Timothy R. Valentic 1 , Jacob C. Milligan 1 , Matthew P. Crump 2 , John Crosby 2 , Shiou-Chuan Tsai 1
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Daunorubicin is a type II polyketide, one of a large class of polyaromatic natural products with anticancer, antibiotic, and antiviral activity. Type II polyketides are formed by the assembly of malonyl-CoA building blocks, though in rare cases, biosynthesis is initiated by the incorporation of a nonmalonyl derived starter unit, which adds molecular diversity to the poly-β-ketone backbone. Priming mechanisms for the transfer of novel starter units onto polyketide synthases (PKS) are still poorly understood. Daunorubicin biosynthesis incorporates a unique propionyl starter unit thought to be selected for by a subclass (“DpsC type”) of priming ketosynthases (KS III). To date, however, no structural information exists for this subclass of KS III enzymes. Although selectivity for self-acylation with propionyl-CoA has previously been implied, we demonstrate that DpsC shows no discrimination for self-acylation or acyl-transfer to the cognate acyl carrier protein, DpsG with short acyl-CoAs. We present five crystal structures of DpsC, including apo-DpsC, acetyl-DpsC, propionyl-DpsC, butyryl-DpsC, and a cocrystal of DpsC with a nonhydrolyzable phosphopantetheine (PPant) analogue. The DpsC crystal structures reveal the architecture of the active site, the molecular determinants for catalytic activity and homology to O-malonyl transferases, but also indicate distinct differences. These results provide a structural basis for rational engineering of starter unit selection in type II polyketide synthases.
中文翻译：
柔红霉素启动酮合酶DpsC的结构和功能研究
柔红霉素是II型聚酮化合物，是具有抗癌，抗生素和抗病毒活性的一大类多环芳族天然产物之一。II型聚酮化合物是通过丙二酰辅酶A构件的组装而形成的，尽管在极少数情况下，生物合成是通过掺入非丙二酰衍生的起始剂单元而引发的，这会增加聚β-酮主链的分子多样性。尚不清楚将新的起始剂单元转移到聚酮化合物合酶（PKS）上的引发机理。柔红霉素的生物合成过程包含一个独特的丙酰基启动子单元，该启动子单元被认为是启动酮合成酶（KS III）的一个子类（“ DpsC型”）所选择。然而，迄今为止，尚无该KS III酶亚类的结构信息。尽管以前已经暗示了用丙酰辅酶A进行自我酰化的选择性，我们证明DpsC对自酰基化或酰基转移至相关的酰基载体蛋白DpsG并带有短酰基CoAs并没有区别。我们介绍了DpsC的五个晶体结构，包括载脂蛋白-DpsC，乙酰基-DpsC，丙酰基-DpsC，丁酰基-DpsC，以及DpsC与不可水解的磷酸泛肽（PPant）类似物的共结晶。DpsC晶体结构揭示了活性位点的结构，催化活性的分子决定因素和与O-丙二酰基转移酶的同源性，但也显示出明显的差异。这些结果为II型聚酮化合物合酶中起动器单元选择的合理工程设计提供了结构基础。
更新日期：2017-12-11
中文翻译：
柔红霉素启动酮合酶DpsC的结构和功能研究
柔红霉素是II型聚酮化合物，是具有抗癌，抗生素和抗病毒活性的一大类多环芳族天然产物之一。II型聚酮化合物是通过丙二酰辅酶A构件的组装而形成的，尽管在极少数情况下，生物合成是通过掺入非丙二酰衍生的起始剂单元而引发的，这会增加聚β-酮主链的分子多样性。尚不清楚将新的起始剂单元转移到聚酮化合物合酶（PKS）上的引发机理。柔红霉素的生物合成过程包含一个独特的丙酰基启动子单元，该启动子单元被认为是启动酮合成酶（KS III）的一个子类（“ DpsC型”）所选择。然而，迄今为止，尚无该KS III酶亚类的结构信息。尽管以前已经暗示了用丙酰辅酶A进行自我酰化的选择性，我们证明DpsC对自酰基化或酰基转移至相关的酰基载体蛋白DpsG并带有短酰基CoAs并没有区别。我们介绍了DpsC的五个晶体结构，包括载脂蛋白-DpsC，乙酰基-DpsC，丙酰基-DpsC，丁酰基-DpsC，以及DpsC与不可水解的磷酸泛肽（PPant）类似物的共结晶。DpsC晶体结构揭示了活性位点的结构，催化活性的分子决定因素和与O-丙二酰基转移酶的同源性，但也显示出明显的差异。这些结果为II型聚酮化合物合酶中起动器单元选择的合理工程设计提供了结构基础。
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