Department of Life Sciences, University of Bath, UK.
Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
FEBS Lett. 2024 Jan;598(2):242-251. doi: 10.1002/1873-3468.14768. Epub 2023 Nov 3.
Human somatic angiotensin-1-converting enzyme (sACE) is composed of a catalytic N-(nACE) and C-domain (cACE) of similar size with different substrate specificities. It is involved in the regulation of blood pressure by converting angiotensin I to the vasoconstrictor angiotensin II and has been a major focus in the development of therapeutics for hypertension. Bioactive peptides from various sources, including milk, have been identified as natural ACE inhibitors. We report the structural basis for the role of two lacototripeptides, Val-Pro-Pro and Ile-Pro-Pro, in domain-specific inhibition of ACE using X-ray crystallography and kinetic analysis. The lactotripeptides have preference for nACE due to altered polar interactions distal to the catalytic zinc ion. Elucidating the mechanism of binding and domain selectivity of these peptides also provides important insights into the functional roles of ACE.
人源体血管紧张素转换酶（sACE）由大小相似但具有不同底物特异性的催化 N 端（nACE）和 C 端（cACE）组成。它通过将血管紧张素 I 转化为血管收缩素 II 参与血压调节，一直是高血压治疗药物开发的主要关注点。已经从各种来源（包括牛奶）中鉴定出具有生物活性的肽作为天然 ACE 抑制剂。我们使用 X 射线晶体学和动力学分析报告了两种乳三肽，缬氨酰-脯氨酰-脯氨酸和异亮氨酰-脯氨酰-脯氨酸，在 ACE 结构域特异性抑制中的作用的结构基础。由于催化锌离子远端的极性相互作用改变，乳三肽优先与 nACE 结合。阐明这些肽的结合机制和结构域选择性也为 ACE 的功能作用提供了重要的见解。
