Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Murat Oz 1, Dietrich Ernst Lorke 2

Affiliations

01 April 2021

-

doi: 10.1016/j.biopha.2020.111193

Abstract

The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.

Keywords: ACE2; ARDS; Angiotensin II; COVID-19; Coronavirus; SARS.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that there are no conflicts of interest.

Figures

Fig. 1 The renin angiotensin system (RAS). The classical RAS consists of the breakdown of Angiotensin I (Ang-I) into Ang-II via ACE, which can bind either to the AT1 (angiotensin type 1) or the AT2 (angiotensin type 2) receptor. Ang-II has a higher affinity for the AT1 receptor. The non-classical RAS consists of conversion of Ang-I into Ang-(1-9) and Ang-II into Ang-(1-7) by ACE2. Ang-(1-7) stimulates the Mas receptor. Bradykinin and [des-Arg9]-bradykinin are degraded by ACE and ACE2, respectively, into pharmacologically inactive peptides.

Fig. 1 The renin angiotensin system (RAS). The classical RAS consists of the breakdown of Angiotensin I (Ang-I) into Ang-II via ACE, which can bind either to the AT1 (angiotensin type 1) or the AT2 (angiotensin type 2) receptor. Ang-II has a higher affinity for the AT1 receptor. The non-classical RAS consists of conversion of Ang-I into Ang-(1-9) and Ang-II into Ang-(1-7) by ACE2. Ang-(1-7) stimulates the Mas receptor. Bradykinin and [des-Arg9]-bradykinin are degraded by ACE and ACE2, respectively, into pharmacologically inactive peptides.

Fig. 2 Schematic presentation of the host cell proteases involved in the cellular entry of SARS-CoV-2. Cell entry of SARS-CoV-2 can proceed via two distinct routes. The first route of activation can be pursued if the SARS-S-activating protease TMPRSS2 is coexpressed with ACE2 on the surface of target cells. Binding to ACE2 and processing by TMPRSS2 (see inset) are believed to allow fusion at the cell surface. Furin is primarily located in late endosomes and the Golgi network. However, it is secreted into the extracellular fluid and can also be trafficked to the cell membrane. The second route involves binding of the virion-associated trimeric S protein of SARS-CoV-2 to ACE2. As a result, the virions are taken up into endosomes, in which the SARS-S protein is cleaved and activated by the pH-dependent cysteine protease cathepsin L and furin. The SARS-S protein can activate ADAM17, which cleaves ACE2, resulting in shedding of ACE2 (soluble ACE2). The pink ovoid structures at the tip of S1 indicate the receptor-binding domains (RBDs).

Fig. 2 Schematic presentation of the host cell proteases involved in the cellular entry of SARS-CoV-2. Cell entry of SARS-CoV-2 can proceed via two distinct routes. The first route of activation can be pursued if the SARS-S-activating protease TMPRSS2 is coexpressed with ACE2 on the surface of target cells. Binding to ACE2 and processing by TMPRSS2 (see inset) are believed to allow fusion at the cell surface. Furin is primarily located in late endosomes and the Golgi network. However, it is secreted into the extracellular fluid and can also be trafficked to the cell membrane. The second route involves binding of the virion-associated trimeric S protein of SARS-CoV-2 to ACE2. As a result, the virions are taken up into endosomes, in which the SARS-S protein is cleaved and activated by the pH-dependent cysteine protease cathepsin L and furin. The SARS-S protein can activate ADAM17, which cleaves ACE2, resulting in shedding of ACE2 (soluble ACE2). The pink ovoid structures at the tip of S1 indicate the receptor-binding domains (RBDs).

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