Department of Biology, College of Science, United Arab Emirates University, PO Box 15551 Al Ain, Abu Dhabi, UAE.
Biomolecules. 2020 Mar 23;10(3):486. doi: 10.3390/biom10030486.
Angiotensin-I converting enzyme (ACE) is a zinc metallopeptidase that has an important role in regulating the renin-angiotensin-aldosterone system (RAAS). It is also an important drug target for the management of cardiovascular diseases. Hemorphins are endogenous peptides that are produced by proteolytic cleavage of beta hemoglobin. A number of studies have reported various therapeutic activities of hemorphins. Previous reports have shown antihypertensive action of hemorphins via the inhibition of ACE. The sequence of hemorphins is highly conserved among mammals, except in camels, which harbors a unique Q>R variation in the peptide. Here, we studied the ACE inhibitory activity of camel hemorphins (LVVYPWTRRF and YPWTRRF) and non-camel hemorphins (LVVYPWTQRF and YPWTQRF). Computational methods were used to determine the most likely binding pose and binding affinity of both camel and non-camel hemorphins within the active site of ACE. Molecular dynamics simulations showed that the peptides interacted with critical residues in the active site of ACE. Notably, camel hemorphins showed higher binding affinity and sustained interactions with all three subsites of the ACE active site. An in vitro ACE inhibition assay showed that the IC of camel hemorphins were significantly lower than the IC of non-camel hemorphins.
血管紧张素转化酶（ACE）是一种锌金属肽酶，在调节肾素-血管紧张素-醛固酮系统（RAAS）中具有重要作用。它也是治疗心血管疾病的重要药物靶点。血红蛋白酶原是通过β血红蛋白的蛋白水解切割产生的内源性肽。许多研究报道了血红蛋白酶原的各种治疗活性。以前的报告表明，血红蛋白酶原通过抑制 ACE 发挥降压作用。除骆驼外，哺乳动物的血红蛋白酶原序列高度保守，在该肽中存在独特的 Q>R 变异。在这里，我们研究了骆驼血红蛋白酶原（LVVYPWTRRF 和 YPWTRRF）和非骆驼血红蛋白酶原（LVVYPWTQRF 和 YPWTQRF）的 ACE 抑制活性。计算方法用于确定 ACE 活性位点内两种骆驼和非骆驼血红蛋白酶原的最可能结合构象和结合亲和力。分子动力学模拟表明，肽与 ACE 活性位点中的关键残基相互作用。值得注意的是，骆驼血红蛋白酶原与 ACE 活性位点的所有三个结合位点表现出更高的结合亲和力和持续相互作用。体外 ACE 抑制测定表明，骆驼血红蛋白酶原的 IC 明显低于非骆驼血红蛋白酶原的 IC。
