Angiotensin-converting enzyme-2 (ACE2): Comparative modeling of the active site, specificity requirements, and chloride dependence
Angiotensin-converting enzyme-2 (ACE2): Comparative modeling of the active site, specificity requirements, and chloride dependence
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DOI：
10.1021/bi035268s
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发表时间：
2003-11-18
期刊：
影响因子：
2.9
通讯作者：
Turner, AJ
中科院分区：
文献类型：
--
作者：
Guy, JL;Jackson, RM;Turner, AJ
血管紧张素转换酶2（ACE 2）是ACE的同源物，是心肾疾病中一个新的潜在重要靶点。基于睾丸ACE的晶体结构，ACE2的活性位点的模型已经被开发，并且表明ACE2的催化机制类似于ACE。ACE（二肽基羧肽酶）和ACE2（羧肽酶）的活性位点之间存在结构差异，这是特异性差异的原因。主要差异发生在配体结合口袋，特别是在S2 '亚位点和肽羧基末端的结合。该模型解释了为什么经典的ACE抑制剂赖诺普利不能与ACE2结合。基于ACE2切割多种生物活性肽的能力，ACE2的蛋白酶特异性的Pro-X-Pro-疏水/碱性的共有序列已经被定义，这得到ACE2模型的支持。二肽Pro-Phe在180 μ M时完全抑制ACE 2活性，血管紧张素II作为底物。与ACE一样，ACE2的氯依赖性是底物特异性的，使得血管紧张素I的水解和合成肽底物Mca-APK（Dnp）在氯离子存在下被激活，而血管紧张素II的裂解被抑制。ACE2模型也提示了氯激活的可能机制。这些分析提供了ACE及其同系物ACE2之间抑制模式和底物特异性差异以及ACE/ACE2活性的氯依赖性的结构见解，对于理解ACE2的功能和调节是有价值的。
Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, represents a new and potentially important target in cardio-renal disease. A model of the active site of ACE2, based on the crystal structure of testicular ACE, has been developed and indicates that the catalytic mechanism of ACE2 resembles that of ACE. Structural differences exist between the active site of ACE (dipeptidyl carboxypeptidase) and ACE2 (carboxypeptidase) that are responsible for the differences in specificity. The main differences occur in the ligand-binding pockets, particularly at the S2' subsite and in the binding of the peptide carboxy-terminus. The model explains why the classical ACE inhibitor lisinopril is unable to bind to ACE2. On the basis of the ability of ACE2 to cleave a variety of biologically active peptides, a consensus sequence of Pro-X-Pro-hydrophobic/basic for the protease specificity of ACE2 has been defined that is supported by the ACE2 model. The dipeptide, Pro-Phe, completely inhibits ACE2 activity at 180 muM with angiotensin II as the substrate. As with ACE, the chloride dependence of ACE2 is substrate-specific such that the hydrolysis of angiotensin I and the synthetic peptide substrate, Mca-APK(Dnp), are activated in the presence of chloride ions, whereas the cleavage of angiotensin II is inhibited. The ACE2 model is also suggestive of a possible mechanism for chloride activation. The structural insights provided by these analyses for the differences in inhibition pattern and substrate specificity among ACE and its homologue ACE2 and for the chloride dependence of ACE/ACE2 activity are valuable in understanding the \function and regulation of ACE2.