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首页> 美国卫生研究院文献>Biochemical Journal >Evaluation of angiotensin-converting enzyme (ACE) its homologue ACE2 and neprilysin in angiotensin peptide metabolism
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Evaluation of angiotensin-converting enzyme (ACE) its homologue ACE2 and neprilysin in angiotensin peptide metabolism

机译：评价血管紧张素转换酶（ACE）其同系物ACE2和中性溶酶在血管紧张素肽代谢中的作用

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In the RAS (renin–angiotensin system), Ang I (angiotensin I) is cleaved by ACE (angiotensin-converting enzyme) to form Ang II (angiotensin II), which has effects on blood pressure, fluid and electrolyte homoeostasis. We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). The activity of the enzyme preparations was determined by active-site titrations using competitive tight-binding inhibitors and fluorogenic substrates. Ang I was effectively cleaved by NEP to Ang (1–7) (kcat/Km of 6.2×105 M−1·s−1), but was a poor substrate for ACE2 (kcat/Km of 3.3×104 M−1·s−1). Ang (1–9) was a better substrate for NEP than ACE (kcat/Km of 3.7×105 M−1·s−1 compared with kcat/Km of 6.8×104 M−1·s−1). Ang II was cleaved efficiently by ACE2 to Ang (1–7) (kcat/Km of 2.2×106 M−1·s−1) and was cleaved by NEP (kcat/Km of 2.2×105 M−1·s−1) to several degradation products. In contrast with a previous report, Ang (1–7), like Ang I and Ang (1–9), was cleaved with a similar efficiency by both the N- and C-domains of ACE (kcat/Km of 3.6×105 M−1·s−1 compared with kcat/Km of 3.3×105 M−1·s−1). The two active sites of ACE exhibited negative co-operativity when either Ang I or Ang (1–7) was the substrate. In addition, a range of ACE inhibitors failed to inhibit ACE2. These kinetic data highlight that the flux of peptides through the RAS is complex, with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate.
机译：在RAS（肾素-血管紧张素系统）中，Ang I（血管紧张素I）被ACE（血管紧张素转化酶）裂解形成Ang II（血管紧张素II），对血压，体液和电解质的均流具有影响。我们已经检查了全长人类ACE，ACE的单独N和C结构域，ACE，ACE2和NEP（neprilysin）的同源物对血管紧张素肽切割的动力学。酶制剂的活性通过使用竞争性紧密结合抑制剂和荧光底物的活性部位滴定来确定。 NEP有效地将Ang I裂解为Ang（1-7）（kcat / Km为6.2×10 5 M -1 ·s -1 ），但它是ACE2的较差底物（kcat / Km为3.3×10 4 M -1 ·s -1 ）。 Ang（1–9）是NEP的较好底物（kcat / Km为3.7×10 5 M -1 ·s -1 与6.8×10 4 M -1 ·s -1 的kcat / Km相比）。 Ang2被ACE2有效裂解为Ang（1–7）（kcat / Km为2.2×10 6 M -1 ·s -1 ），并被NEP（kcat / Km为2.2×10 5 M -1 ·s -1 ）裂解。与以前的报告相比，Ang（1–7）像Ang I和Ang（1–9）一样，被ACE的N和C域均以类似的效率分裂（kcat / Km为3.6×10 5 M -1 ·s -1 与kcat / Km为3.3×10 5 M -1 ·s -1 ）。当Ang I或Ang（1–7）作为底物时，ACE的两个活性位点均表现出负的协同作用。另外，一系列ACE抑制剂不能抑制ACE2。这些动力学数据表明，肽通过RAS的通量是复杂的，ACE，ACE2和NEP的水平决定了血管收缩或血管扩张将占主导地位。

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