Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Biological Resources and Post-harvest Division, Japan International Research Center for Agricultural Sciences, 1-1 Ohwashi, Tsukuba, Ibaraki, 305-8686, Japan.
Nat Commun. 2020 Feb 26;11(1):1058. doi: 10.1038/s41467-020-14867-z.
Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.
血管紧张素转换酶 2（ACE2）在心血管生理学和病理学中起着关键作用，目前正在临床评估用于治疗急性肺衰竭。在这里，我们发现来源于芽孢杆菌 B38 的羧肽酶 B38-CAP 是一种 ACE2 样酶，可以降低小鼠体内血管紧张素 II 的水平。在蛋白质 3D 结构分析中，B38-CAP 同系物与哺乳动物 ACE2 具有结构相似性，但序列同一性较低。在体外，重组 B38-CAP 蛋白可催化血管紧张素 II 转化为血管紧张素 1-7 以及其他已知的 ACE2 靶肽。B38-CAP 的治疗可抑制血管紧张素 II 诱导的高血压、心脏肥大和纤维化。此外，B38-CAP 抑制了压力超负荷诱导的病理性肥大、心肌纤维化和心脏功能障碍。我们的数据确定了细菌 B38-CAP 是一种 ACE2 样羧肽酶，表明进化塑造了一种细菌羧肽酶成为人类 ACE2 样酶。细菌工程可用于设计用于高血压和心力衰竭的改良蛋白药物。
