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

Takafumi Minato, Satoru Nirasawa (), Teruki Sato, Tomokazu Yamaguchi, Midori Hoshizaki, Tadakatsu Inagaki, Kazuhiko Nakahara, Tadashi Yoshihashi, Ryo Ozawa, Saki Yokota, Miyuki Natsui, Souichi Koyota, Taku Yoshiya, Kumiko Yoshizawa-Kumagaye, Satoru Motoyama, Takeshi Gotoh, Yoshikazu Nakaoka, Josef M. Penninger, Hiroyuki Watanabe, Yumiko Imai, Saori Takahashi and Keiji Kuba ()
Additional contact information
Takafumi Minato: Akita University Graduate School of Medicine
Satoru Nirasawa: Japan International Research Center for Agricultural Sciences
Teruki Sato: Akita University Graduate School of Medicine
Tomokazu Yamaguchi: Akita University Graduate School of Medicine
Midori Hoshizaki: National Institute of Biomedical Innovation, Health and Nutrition
Tadakatsu Inagaki: Research Institute National Cerebral and Cardiovascular Center
Kazuhiko Nakahara: Japan International Research Center for Agricultural Sciences
Tadashi Yoshihashi: Japan International Research Center for Agricultural Sciences
Ryo Ozawa: Akita University Graduate School of Medicine
Saki Yokota: Akita University
Miyuki Natsui: Akita University Graduate School of Medicine
Souichi Koyota: Akita University
Taku Yoshiya: Peptide Institute, Inc.
Kumiko Yoshizawa-Kumagaye: Peptide Institute, Inc.
Satoru Motoyama: Akita University Graduate School of Medicine
Takeshi Gotoh: Akita University
Yoshikazu Nakaoka: Research Institute National Cerebral and Cardiovascular Center
Josef M. Penninger: IMBA -Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Campus Vienna BioCenter
Hiroyuki Watanabe: Akita University Graduate School of Medicine
Yumiko Imai: National Institute of Biomedical Innovation, Health and Nutrition
Saori Takahashi: Akita Research Institute of Food and Brewing
Keiji Kuba: Akita University Graduate School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14867-z

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