Xanthone Receptors as Oxyanion-Hole Mimics in Artificial Enzymes
Xanthone Receptors as Oxyanion-Hole Mimics in Artificial Enzymes
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人工酶中作为氧阴离子空穴模拟物的呫吨酮受体
DOI：
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
J. R. Morán
中科院分区：
文献类型：
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作者：
L. Simón;Francisco M. Muñiz;Silvia Sáez;C. Raposo;F. Sanz;J. R. Morán
已经制备了不同的基于氧杂蒽酮的内酯和内酰胺受体（2 ± 10），并讨论了这些化合物模拟已知的酶-氧阴离子-孔×结构的可行性。发现受体的自缔合对复合物的形成造成严重的缺陷。受体二聚体的X射线晶体结构使我们能够理解它们自缔合的原因并改进催化剂的设计。对吡咯烷与不饱和内酯的亲核加成反应进行了催化活性测试。由于所得配合物在有机溶剂中的作用非常弱，因此开发了新的内酰胺受体，这些受体表现出更好的稳定性，并研究了它们的催化活性。导论.± H键在酶催化中起着重要作用（1）。在过去的十年中，所谓的氧阴离子空穴经常被发现作为水解酶样酶的结构基序（2）。含氧阴离子空穴由两个或更多个H键供体（通常是来自酶骨架的两个肽NH基团）组成，其朝向底物中的O原子（通常是CO基团），其随着酶促反应的发生而积累电子密度。过渡态中氢键稳定性的增加降低了反应的能垒，增强了催化作用。在寻找能够模拟酶行为的有机受体的过程中，设计能够发挥氧阴离子空穴作用的结构将是非常有趣的。酶如蛋白酶、脂肪酶、酯酶、脱卤酶、过氧化物酶和环氧化物水解酶显示氧阴离子空穴结构，并且有人认为这种结构相似性可能意味着这些酶可能具有共同的祖先（2）。烯酰± CoA水合酶属于这个酶家族。Bahnson等人（3）描述了与4-（N，N-二甲基氨基）肉桂酰基± CoA结合的大鼠肝脏烯酰基± CoA水合酶的X射线结构（PDB条目1 EY 3）。活性位点和底物处的选定氨基酸如图1（左）所示。作者在另一篇文章（4）中也讨论了含氧阴离子空穴在催化中的重要作用。氧杂蒽酮受体1的结构由X射线研究已知（参见下文）。在图1（右）中，我们将该结构与烯酰± CoA水合酶活性位点的结构重叠。除了结构上的相似性外，芳香族酰胺有望比脂肪族酰胺产生更强的氢键，这将增加催化活性。然而，合成的可用性、在反应条件下的稳定性、溶解性
Different xanthone-based receptors (2 ± 10) for lactones and lactams have been prepared, and the feasibility of these compounds to mimic the known enzymatic −oxyanion-hole× structure is discussed. The self- association of the receptors was found to pose a serious drawback for complex formation. X-Ray crystal structures of receptor dimers allowed us to understand the reasons for their self-association and to improve the design of the catalysts. The catalytic activity of the receptors has been tested towards the nucleophilic addition of pyrrolidine to unsaturated lactones. Since the resulting complexes were very weak in organic solvents, new receptors were developed for lactams, which showed better stabilities, and their catalytic activities were studied. Introduction. ± H-Bonds play an important role in enzymatic catalysis (1). Over the last decade, the so-called oxyanion hole has frequently been found as a structural motif in hydrolase-like enzymes (2). The oxyanion hole consists of two or more H-bond donors (usually two peptide NH groups from the backbone of the enzyme) oriented towards an O-atom in the substrate (usually a CO group), which accumulates electron density as the enzymatic reaction takes place. The increased stability of the H- bonds in the transition state reduces the energy barrier of the reaction, enhancing catalysis. In the search for organic receptors able to mimic the behavior of enzymes, it would be of great interest to design structures that could play the role of the oxyanion hole. Enzymes such as proteases, lipases, esterases, dehalogenases, peroxidases, and epoxide hydrolases display the oxyanion-hole structure, and it has been suggested that this structural similarity may imply that these enzymes may have had a common ancestor (2). Enoyl ± CoA hydratase belongs to this family of enzymes. Bahnson et al. (3) described the X-ray structure of rat liver enoyl ± CoA hydratase bound to 4-(N,N- dimethylamino)cinnamoyl ± CoA (PDB entry 1EY3). Selected amino acids at the active site and the substrate are shown in Fig. 1 (left). This author also discussed the important role of the oxyanion hole in catalysis in another article (4). The structure of the xanthone receptor 1 is known from an X-ray study (vide infra). In Fig. 1 (right), we have overlaid this structure with that of the enoyl ± CoA hydratase active site. Besides the structural similarity, aromatic amides are expected to give stronger H-bonds than aliphatic ones, which should increase the catalytic activity. Nevertheless, synthetic availability, stability under the reaction conditions, solubility
影响因子：
2.9
作者：
Bahnson, BJ;Anderson, VE;Petsko, GA
通讯作者：
Petsko, GA
影响因子：
56.9
作者：
CLELAND, WW;KREEVOY, MM
通讯作者：
KREEVOY, MM