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The Angiotensin-converting Enzyme 2 (ACE2) Family

ACE2 is a receptor for the COVID-19-causing virus, CoV-2. It is cleaved by transmembrane proteases during host cell infection, thus reducing its activities. ACE2 is a relevant player in the renin-angiotensin system (RAS), counterbalancing the deleterious effects of angiotensin II. Intestinal ACE2 functions as a chaperone for the amino acid transporter B(0)AT1 (TC# 2.A.22.6.3). ACE2 may serve as a chaperone protein, stabilizing the neutral amino acid transporter, B(0)AT1 (Sharma et al. 2020). ACE2-mediated dysregulation of SGLT1 in the intestinal epithelium links it to the pathogenesis of diabetes mellitus which can be a reason for the associated mortality in COVID-19 patients with diabetes (Kumar et al. 2020). The major route of entry for SARS-CoV-2 into human cells is by means of the ACE2) receptor. This zinc-containing carboxypeptidase and membrane-integral surface receptor is ubiquitous and widely expressed in multiple cell types (Zhao et al. 2021). PDZ-containing proteins are targeted by the ACE2 receptor (Caillet-Saguy and Wolff 2021). The ACE2 receptor and its protease, TMPRSS2, are coexpressed in testicular cells, and the CD147 receptor and its protease CTSL are exoressed in Leydig and Sertoli cells (Ribeiro et al. 2023).

Possibly, the B(0)AT1/ACE2 complex in the intestinal epithelium regulates the gut microbiota (GM) composition and function, with important repercussions on local and systemic immune responses against pathogenic agents such as viruses. Productive infection of SARS-CoV-2 in ACE2+ mature human enterocytes and patients' GM dysbiosis has been demonstrated. Viana et al. 2020 outlined the evidence linking abnormal ACE2 functions with the poor outcomes (higher disease severity and mortality rate) in COVID-19 patients with pre-existing age-related co-morbidities and addresses a possible role for GM dysbiosis. There are therapeutic possibilities based on these pathways (Viana et al. 2020). Atrial and ventricular cardiomyocytes have increased levels of ACE2 and other proteins that facilitate viral entry, and are therefore susceptible to SARS-CoV-2 infection (Yang et al. 2021).  Lou et al. 2023 showed the effectiveness of a knowledge graph-based approach in potential target discovery and drug repurposing for coronaviruses. This approach may be extended to other viruses or diseases for biomedical knowledge discovery and relevant applications (Lou et al. 2023).

ACE2 is a transmembrane protein and as a soluble catalytic ectodomain of ACE2, also known as the soluble ACE2 that can be found in plasma and other body fluids. ACE2 regulates the local actions of the renin-angiotensin system in cardiovascular tissues, and the ACE2/Angiotensin 1-7 axis exerts protective actions in cardiovascular disease (García-Escobar et al. 2021). Increasing soluble ACE2 is associated with heart failure, cardiovascular disease, and cardiac remodelling. García-Escobar et al. 2021 reviewed of the molecular structure and biochemical functions of ACE2, and updated the evidence, clinical applications, and emerging potential therapies with the ACE2 in heart failure, cardiovascular disease, lung injury, and COVID-19 infection. Antihypertensive activities of two ACE-renin inhibitory peptides has been reported (Ma et al. 2021). Angiotensin converting enzyme 2 (ACE-2), transmembrane serine protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells including astrocytes in the blood brain barrier (BBB) (Malik et al. 2023).




References associated with 8.A.139 family:

Caillet-Saguy, C. and N. Wolff. (2021). PDZ-Containing Proteins Targeted by the ACE2 Receptor. Viruses 13:. 34835087
García-Escobar, A., S. Jiménez-Valero, G. Galeote, A. Jurado-Román, J. García-Rodríguez, and R. Moreno. (2021). The soluble catalytic ectodomain of ACE2 a biomarker of cardiac remodelling: new insights for heart failure and COVID19. Heart Fail Rev. [Epub: Ahead of Print] 33404999
Lou, P., A. Fang, W. Zhao, K. Yao, Y. Yang, and J. Hu. (2023). Potential Target Discovery and Drug Repurposing for Coronaviruses: Study Involving a Knowledge Graph-Based Approach. J Med Internet Res 25: e45225. 37862061
Ma, K., Y. Wang, M. Wang, Z. Wang, X. Wang, X. Ju, and R. He. (2021). Antihypertensive activity of the ACE-renin inhibitory peptide derived from protein. Food Funct 12: 8994-9006. 34382048
Malik, J.R., A. Acharya, S.N. Avedissian, S.N. Byrareddy, C.V. Fletcher, A.T. Podany, and S.R. Dyavar. (2023). ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics. Int J Mol Sci 24:. 37239978
Ribeiro, M.R., A.M. Calado, &.#.1.9.4.;. Alves, R. Pereira, M. Sousa, and R. Sá. (2023). Spatial Distribution of SARS-CoV-2 Receptors and Proteases in Testicular Cells. J Histochem Cytochem 71: 169-197. 37026452
Sharma, R.K., B.R. Stevens, A.G. Obukhov, M.B. Grant, G.Y. Oudit, Q. Li, E.M. Richards, C.J. Pepine, and M.K. Raizada. (2020). ACE2 (Angiotensin-Converting Enzyme 2) in Cardiopulmonary Diseases: Ramifications for the Control of SARS-CoV-2. Hypertension 76: 651-661. 32783758
Viana, S.D., S. Nunes, and F. Reis. (2020). ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities - Role of gut microbiota dysbiosis. Ageing Res Rev 62: 101123. [Epub: Ahead of Print] 32683039
Yang, J., T. Chen, and Y. Zhou. (2021). Mediators of SARS-CoV-2 entry are preferentially enriched in cardiomyocytes. Hereditas 158: 4. 33397514
Zhao, Y., W. Li, and W. Lukiw. (2021). Ubiquity of the SARS-CoV-2 receptor ACE2 and upregulation in limbic regions of Alzheimer''s disease brain. Folia Neuropathol 59: 232-238. 34628788