College of Pharmacy, University of Utrecht, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands; College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, 33328, United States.
Peptides. 2021 Mar;137:170477. doi: 10.1016/j.peptides.2020.170477. Epub 2021 Jan 2.
After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-AspAng II, 2-8 heptapeptide) and Ang IV (des-Aspdes-ArgAng II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest K) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 μM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.
经过几十年因其对心血管的不良影响、促炎和致纤维化作用而声名狼藉，血管紧张素转换酶 2（ACE2）于 2000 年被发现，使得肾素-血管紧张素系统（RAS）开始被重新审视。这种单羧肽酶以其代谢血管紧张素（Ang）II 生成 Ang 1-7 的能力而闻名，可对抗 Ang II 介导的 AT1 血管紧张素 II 受体的不良作用。Ang 肽通常被认为是被氨肽酶代谢的，由此衍生出 Ang III（去天冬酰基 Ang II，2-8 七肽）和 Ang IV（去天冬酰基去精氨酸 Ang II，3-8 六肽）的命名。本报告比较了重组人 ACE2（rhACE2）代谢 Ang III、Ang IV 和 Ang V（4-8 五肽）形成相应的去 ω-苯丙氨酸代谢物的能力，与 Ang II 相比。rhACE2 对 Ang III 的亲和力最高（最低 K），其次是 Ang II∼Ang V，其次是 Ang IV。然而，rhACE2 对 Ang IV 的代谢 Kcat 最高，其次是 Ang V、Ang III 和 Ang II。酶学效率（Kcat/Km）对 Ang V 和 Ang III 最高，其次是 Ang IV，对 Ang II 最低。作为一种锌金属肽酶，ACE2 其活性位点需要一个锌分子进行催化。本报告还记录了超过 10 μM 的锌浓度抑制 ACE2 活性。这些观察结果将 ACE2 的功能意义扩展到包括 Ang III、Ang IV 和 Ang V 的代谢失活，再次强调了监测锌摄入量以维持代谢平衡的重要性。
