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evolution
Spike protein of SARS-CoV-2 exhibits the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Pangolin (Manis javanica) ACE2 shows the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 is much lower despite its high sequence similarity to hACE2. ACE2 species in the upper half of the predicted affinity range (Macaca fascicularis, Mesocricetus auratus, Canis luparis, Mustela putorius furot, Felis catus) are permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility
physiological function
ACE2 knockout mice display elevated levels of ER stress, while ACE2 overexpressing db/db mice show reduced ER stress in liver
physiological function
angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2 of certain species can be utilized by SARS-CoV-2. SARS-CoV-2 tends to utilize ACE2 of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2. SARS-CoV-2 has a high genetic relationship with a bat coronavirus (BatCoV RaTG13) with a 96% genomic nucleotide sequence identity. The close phylogenetic relationship to Bat RaTG13 provides evidence for a bat origin of SARS-CoV-2. Direct transmission of the virus from bats to humans is unlikely due to the lack of direct contact between bats and humans (in Wuhan, China). There are probably intermediate hosts transmitting SARS-CoV-2 to humans. Combined phylogenetic analysis and critical site marking is used to predict the utilizing capability of ACE2 from different animal species by SARS-CoV-2. It is confirmed that pangolin (Manis javanica), cat (Felis catus), cow (Bos taurus), buffalo (Bubalus bubalis), goat (Capra hircus), sheep (Ovis aries) and pigeon (Columba livia) ACE2 might be utilized by SARS-CoV-2, indicating potential interspecies transmission of the virus from bats to these animals and among these animals
physiological function
deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout mice. Oxidative stress and inflammation are also aggravated in ACE2 knockout mice. Overexpression of ACE2 improves fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes are up-regulated
physiological function
exogenous ACE2 attenuates bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of angiotensinogen. ACE2 decreases the apoptosis index and leukocyte common antigen levels and ameliorates the dynamic change in surfactant-associated protein SP-A level. Reductions of TGF-beta1 and alpha-SMA are also found in ACE2-treated mice
physiological function
in ACE2 knockout mice, hypotensive action of peptides pyr-apelin 13 and apelin 17 is potentiated, with a corresponding greater elevation in plasma apelin levels. Pyr-apelin 13 and apelin 17 rescue contractile function in a myocardial ischemia-reperfusion model, while ACE2 cleavage products, pyr-apelin 12 and 16, are devoid of these cardioprotective effects. Pharmacological inhibition of ACE2 potentiates the vasodepressor action of apelin peptides. Loss of C-terminal phenylalanine attenuates apelin peptide physiological effects
physiological function
interaction between SARS-CoV-2 and ACE2. Most mouse ACE2 receptors (including rats and mice) show higher binding free energies than the human ACE2, indicating weaker binding to the SARS-CoV-2 spike. The mole ACE2 has a similar binding free energy to the human ACE2 due to their high sequence identity at the binding interface to the SARS-CoV-2 spike protein
malfunction
-
angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice
malfunction
-
loss of ACE2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction, MI, overview. ACE2 deficiency leads to increased matrix metalloproteinases 2 and 9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-gamma, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways
malfunction
-
ACE2 deficiency increases the severity of H7N9-induced lung injury in a mouse model
malfunction
-
ACE2 knockout mice are more susceptible than the wild-type mice to high-fat diet-induced beta cell dysfunction. The TUNEL-positive area of the pancreatic islets and the expression levels of IL-1beta and iNOS are markedly increased in the ACE2 knockout mice compared with their wild-type littermates. The Mas-silenced MS-1 cells are more sensitive to palmitate-induced dysfunction and apoptosis in vitro
malfunction
-
ACE2 over-expression in the brain decreases Ang-II mediated cardiac hypertrophy and collagen deposition, reduces urinary norepinephrine levels and partially protectes syn-hACE2 transgenic (SA) mice, in which the human ACE2 transgene is selectively targeted to neurons, from sympathetic-mediated cardiac hypertrophy and fibrosis
malfunction
-
genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice. Administration of recombinant ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice
malfunction
-
mice infected with influenza H7N9 virus downregulate ACE2 protein markedly on day 3 after infection
physiological function
-
ACE2 is a component of the brain renin-angiotensin system participating in the central regulation of blood pressure
physiological function
-
ACE2 is a monocarboxypeptidase that metabolizes Ang II into Ang 1-7, thereby functioning as a negative regulator of the renin-angiotensin system
physiological function
-
ACE2 is a regulator of the renin-angiotensin system
physiological function
-
ACE2 plays a critical role in influenzaA(H7N9) virus-induced acute lung injury
physiological function
-
ACE2 plays an important role in H5N1 virus-induced ALI
physiological function
-
ACE2/angiotensin (1-7)/Mas axis protects the function of pancreatic beta cells by improving the function of islet microvascular endothelial cells
physiological function
-
at pH values below 6, formation of angiotensin (1-7) in ACE2 knockout mice is similar to that in wild-type mice. The prolyl carboxypeptidase-prolyl endopeptidase inhibitor Z-prolyl-prolinal reduces angiotensin (1-7) formation in ACE2 knockout mice. ACE2 metabolizes angiotensin II in the kidney at neutral and basic pH, while prolyl carboxypeptidase catalyzes the same reaction at acidic pH
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Elased, K.M.; Cunha, T.S.; Gurley, S.B.; Coffman, T.M.; Morris, M.
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Homo sapiens, Mus musculus
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Li, X.; Molina-Molina, M.; Abdul-Hafez, A.; Uhal, V.; Xaubet, A.; Uhal, B.D.
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Mus musculus
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Mus musculus
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Mus musculus (Q8R0I0), Mus musculus
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Expression of feline angiotensin converting enzyme 2 and its interaction with SARS-CoV S1 protein
Res. Vet. Sci.
84
494-496
2008
Felis silvestris (Q56H28), Rattus norvegicus (Q5EGZ1), Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1), Homo sapiens
brenda
Feng, Y.; Yue, X.; Xia, H.; Bindom, S.M.; Hickman, P.J.; Filipeanu, C.M.; Wu, G.; Lazartigues, E.
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102
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2008
Mus musculus (Q8R0I0), Mus musculus
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Xia, H.; Lazartigues, E.
Angiotensin-converting enzyme 2 in the brain: properties and future directions
J. Neurochem.
107
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2008
Rattus norvegicus (Q5EGZ1), Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
Iwata, M.; Silva Enciso, J.E.; Greenberg, B.H.
Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme
Am. J. Physiol. Cell Physiol.
297
C1318-C1329
2009
Cricetulus griseus, Mus musculus
brenda
Kassiri, Z.; Zhong, J.; Guo, D.; Basu, R.; Wang, X.; Liu, P.P.; Scholey, J.W.; Penninger, J.M.; Oudit, G.Y.
Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction
Circ. Heart Fail.
2
446-455
2009
Mus musculus
brenda
Xia, H.; Feng, Y.; Obr, T.D.; Hickman, P.J.; Lazartigues, E.
Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice
Hypertension
53
210-216
2009
Mus musculus
brenda
Fraga-Silva, R.A.; Sorg, B.S.; Wankhede, M.; Dedeugd, C.; Jun, J.Y.; Baker, M.B.; Li, Y.; Castellano, R.K.; Katovich, M.J.; Raizada, M.K.; Ferreira, A.J.
ACE2 activation promotes antithrombotic activity
Mol. Med.
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210-215
2010
Mus musculus, Rattus norvegicus
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Lu, C.L.; Wang, Y.; Yuan, L.; Li, Y.; Li, X.Y.
The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects the function of pancreatic beta cells by improving the function of islet microvascular endothelial cells
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34
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Mus musculus
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Liu, S.; Liu, J.; Miura, Y.; Tanabe, C.; Maeda, T.; Terayama, Y.; Turner, A.J.; Zou, K.; Komano, H.
Conversion of Abeta43 to Abeta40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme
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Homo sapiens, Mus musculus
brenda
Zou, Z.; Yan, Y.; Shu, Y.; Gao, R.; Sun, Y.; Li, X.; Ju, X.; Liang, Z.; Liu, Q.; Zhao, Y.; Guo, F.; Bai, T.; Han, Z.; Zhu, J.; Zhou, H.; Huang, F.; Li, C.; Lu, H.; Li, N.; Li, D.; Jin, N.; Penninger, J.M.; Jiang, C.
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Nat. Commun.
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3594
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Mus musculus
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Feng, Y.; Hans, C.; McIlwain, E.; Varner, K.J.; Lazartigues, E.
Angiotensin-converting enzyme 2 over-expression in the central nervous system reduces angiotensin-II-mediated cardiac hypertrophy
PLoS ONE
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e48910
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Mus musculus
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Xiao, F.; Zimpelmann, J.; Agaybi, S.; Gurley, S.B.; Puente, L.; Burns, K.D.
Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells
PLoS ONE
9
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Mus musculus
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Sci. Rep.
4
7027
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Mus musculus
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Grobe, N.; Weir, N.M.; Leiva, O.; Ong, F.S.; Bernstein, K.E.; Schmaier, A.H.; Morris, M.; Elased, K.M.
Identification of prolyl carboxypeptidase as an alternative enzyme for processing of renal angiotensin II using mass spectrometry
Am. J. Physiol. Cell Physiol.
304
C945-C953
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Mus musculus
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Wang, L.; Wang, Y.; Yang, T.; Guo, Y.; Sun, T.
Angiotensin-converting enzyme 2 attenuates bleomycin-induced lung fibrosis in mice
Cell. Physiol. Biochem.
36
697-711
2015
Mus musculus (Q8R0I0), Mus musculus
brenda
Cao, X.; Song, L.; Zhang, Y.; Li, Q.; Shi, T.; Yang, F.; Yuan, M.; Xin, Z.; Yang, J.
Angiotensin-converting enzyme 2 inhibits endoplasmic reticulum stress-associated pathway to preserve nonalcoholic fatty liver disease
Diabetes Metab. Res. Rev.
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Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
Tian, X.; Li, C.; Huang, A.; Xia, S.; Lu, S.; Shi, Z.; Lu, L.; Jiang, S.; Yang, Z.; Wu, Y.; Ying, T.
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9
382-385
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Mus musculus (Q8R0I0)
brenda
Wang, W.; McKinnie, S.; Farhan, M.; Paul, M.; McDonald, T.; McLean, B.; Llorens-Cortes, C.; Hazra, S.; Murray, A.; Vederas, J.; Oudit, G.
Angiotensin-converting enzyme 2 metabolizes and partially inactivates pyr-apelin-13 and apelin-17 Physiological effects in the cardiovascular system
Hypertension
68
365-377
2016
Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1), Homo sapiens
brenda
Xiao, F.; Burns, K.D.
Measurement of angiotensin converting enzyme 2 activity in biological fluid (ACE2)
Methods Mol. Biol.
1527
101-115
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Mus musculus (Q8R0I0), Mus musculus, Homo sapiens (Q9BYF1), Homo sapiens
brenda
Sriramula, S.; Pedersen, K.B.; Xia, H.; Lazartigues, E.
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Mus musculus (Q8R0I0)
brenda
Qiu, Y.; Zhao, Y.B.; Wang, Q.; Li, J.Y.; Zhou, Z.J.; Liao, C.H.; Ge, X.Y.
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Microbes Infect.
22
221-225
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Columba livia (A0A2I0MLI2), Sus scrofa (K7GLM4), Felis catus (Q56H28), Paguma larvata (Q56NL1), Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1), Homo sapiens, Rhinolophus sinicus (U5WHY8), Capra hircus (W6CG84), Bos taurus (XP_005228485.1), Bubalus bubalis (XP_006041602.1), Ovis aries (XP_011961657.1), Manis javanica (XP_017505752.1)
brenda
Cao, X.; Yang, F.; Shi, T.; Yuan, M.; Xin, Z.; Xie, R.; Li, S.; Li, H.; Yang, J.K.
Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis
Sci. Rep.
6
21592
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Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
Piplani, S.; Singh, P.K.; Winkler, D.A.; Petrovsky, N.
In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin
Sci. Rep.
11
13063
2021
Mesocricetus auratus (A0A1U7QTA1), Macaca fascicularis (A0A2K5X283), Equus caballus (F6V9L3), Canis lupus familiaris (J9P7Y2), Canis lupus familiaris, Bos taurus (Q2HJI5), Mustela putorius furo (Q2WG88), Mustela putorius furo, Felis catus (Q56H28), Paguma larvata (Q56NL1), Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1), Homo sapiens, Rhinolophus sinicus (U5WHY8), Ophiophagus hannah (V8NIH2), Panthera tigris (XP_007090142), Manis javanica (XP_017505752.1)
brenda
Chen, P.; Wang, J.; Xu, X.; Li, Y.; Zhu, Y.; Li, X.; Li, M.; Hao, P.
Molecular dynamic simulation analysis of SARS-CoV-2 spike mutations and evaluation of ACE2 from pets and wild animals for infection risk
Comput. Biol. Chem.
96
107613
2022
Manis javanica, Paguma larvata (Q56NL1), Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
Sepe, S.; Rossiello, F.; Cancila, V.; Iannelli, F.; Matti, V.; Cicio, G.; Cabrini, M.; Marinelli, E.; Alabi, B.R.; di Lillo, A.; Di Napoli, A.; Shay, A.W.; Tripodo, C.; d'Adda di Fagagna, F.
DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging
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23
e53658
2022
Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
de Bruin, N.; Schneider, A.K.; Reus, P.; Talmon, S.; Ciesek, S.; Bojkova, D.; Cinatl, J.; Lodhi, I.; Charlesworth, B.; Sinclair, S.; Pennick, G.; Laughey, W.F.; Gribbon, P.; Kannt, A.; Schiffmann, S.
Ibuprofen, flurbiprofen, etoricoxib or paracetamol do not influence ACE2 expression and activity in vitro or in mice and do not exacerbate in-vitro SARS-CoV-2 infection
Int. J. Mol. Sci.
23
1049
2022
Mus musculus (Q8R0I0), Homo sapiens (Q9BYF1)
brenda
Vo, T.; Paudel, K.; Choudhary, I.; Patial, S.; Saini, Y.
Ozone exposure upregulates the expression of host susceptibility protein TMPRSS2 to SARS-CoV-2
Sci. Rep.
12
1357
2022
Mus musculus (Q8R0I0)
brenda