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Nat Commun. 2020 Feb 26;11(1):1058. doi: 10.1038/s41467-020-14867-z.

B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction.

Author information

1
Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
2
Biological Resources and Post-harvest Division, Japan International Research Center for Agricultural Sciences, 1-1 Ohwashi, Tsukuba, Ibaraki, 305-8686, Japan. stnirasa@affrc.go.jp.
3
Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, Akita, Japan.
4
Laboratory of Regulation of Intractable Infectious Diseases, National Institute of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
5
Department of Vascular Physiology, Research Institute National Cerebral and Cardiovascular Center, 6-1 Kishibe Shinmachi, Suita, Osaka, 564-8565, Japan.
6
Biological Resources and Post-harvest Division, Japan International Research Center for Agricultural Sciences, 1-1 Ohwashi, Tsukuba, Ibaraki, 305-8686, Japan.
7
Department of Materials Science, Applied Chemistry Course, Graduate School of Engineering Science, Akita University, 1-1 Tegatagakuen-machi, Akita, 010-8502, Japan.
8
Molecular Medicine Laboratory, Bioscience Education and Research Support Center, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.
9
Peptide Institute, Inc., 7-2-9 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
10
Department of Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
11
IMBA -Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Campus Vienna BioCenter, Vienna, 1030, Austria.
12
Department of Medical Genetics, Life Science Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
13
Akita Research Institute of Food and Brewing, 4-26 Sanuki, Arayamachi, Akita, 010-1623, Japan.
14
Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan. kuba@med.akita-u.ac.jp.

Abstract

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.

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