Sturrock E D, Natesh R, van Rooyen J M, Acharya K R
Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, 7925, Observatory, Cape Town, South Africa.
Cell Mol Life Sci. 2004 Nov;61(21):2677-86. doi: 10.1007/s00018-004-4239-0.
Angiotensin-converting enzyme (ACE) is a zinc- and chloride-dependent metallopeptidase that plays a vital role in the metabolism of biologically active peptides. Until recently, much of the inhibitor design and mechanism of action of this ubiquitous enzyme was based on the structures of carboxypeptidase A and thermolysin. When compared to the recently solved structures of the testis isoform of ACE (tACE) and its Drosophila homologue (AnCE), carboxypeptidase A showed little structural homology outside of the active site, while thermolysin revealed significant but less marked overall similarity. The ellipsoid-shaped structure of tACE, which has a preponderance of alpha-helices, is characterised by a core channel that has a constriction approximately 10 A from its opening where the zinc-binding active site is located. Comparison of the native protein with the inhibitor-bound form (lisinopril-tACE) does not reveal any striking differences in the conformation of the inhibitor binding site, disfavouring an open and closed configuration. However, the inhibitor complex does provide insights into the network of hydrogen-bonding and ionic interactions in the active site as well as the mechanism of ACE substrate hydrolysis. The three-dimensional structure of ACE now paves the way for the rational design of a new generation of domain-selective ACE inhibitors.
血管紧张素转换酶（ACE）是一种依赖锌和氯的金属肽酶，在生物活性肽的代谢中起着至关重要的作用。直到最近，这种普遍存在的酶的许多抑制剂设计和作用机制都是基于羧肽酶A和嗜热菌蛋白酶的结构。与最近解析出的ACE睾丸同工型（tACE）及其果蝇同源物（AnCE）的结构相比，羧肽酶A在活性位点之外几乎没有结构同源性，而嗜热菌蛋白酶则显示出显著但不太明显的整体相似性。tACE呈椭球形结构，以α螺旋为主，其特征是有一个核心通道，在距其开口约10埃处有一个收缩处，锌结合活性位点位于此处。将天然蛋白与抑制剂结合形式（赖诺普利-tACE）进行比较，未发现抑制剂结合位点的构象有任何显著差异，不支持开放和闭合构型。然而，抑制剂复合物确实为活性位点中的氢键和离子相互作用网络以及ACE底物水解机制提供了见解。ACE的三维结构现在为新一代结构域选择性ACE抑制剂的合理设计铺平了道路。
