Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.
Entry of SARS-CoV-2 into cells
The entry of SARS-CoV-2 into cells is mediated by the efficient binding of the spike (S) viral protein, a 1273 amino acid long protein which belongs to the viral envelope and protrudes outwards with a ‘corona’ like appearance, to the angiotensin converting enzyme 2 (ACE2) receptors. [2,3]
The ACE2 receptor, discovered by two independent groups in year 2000, [4,5] is a trans-membrane type I glycoprotein (mono-carboxypeptidase) composed by 805 amino acids which uses a single extracellular catalytic domain to remove one single amino acid from the octapeptide angiotensin II to generate angiotensin1-7. ACE2 receptor also converts angiotensin I into angiotensin1-9, which in turn is converted to angiotensin1-7 by ACE and neprilisin (Figure 1 ). The catalytic efficiency of ACE2 is 400 times higher on angiotensin II than on angiotensin I. [6] ACE2 shows a 40% structural identity to ACE, [4] although ACE-inhibitors do not block ACE2 because of the different conformational structure of the catalytic site.
ACE2 mediates the cell entry of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. [7] Notably, SARS-CoV and Sars-CoV2 share a 76% identity in the amino acid sequence, [8] thereby explaining the propensity of these viruses for binding with ACE2. Some structural variations of human ACE2 have been identified that are characterized by a lower binding affinity with the spike viral protein, with potential protective implications. [9] The first step of viral entry process is the binding of the N-terminal portion of the viral protein unit S1 to a pocket of the ACE2 receptor. The second step, which is believed to be of utmost importance for viral entry, is the protein cleavage between the S1 and S2 units, which is operated by the receptor transmembrane protease serine 2 (TMPRSS2), a member of the Hepsin/TMPRSS subfamily. [10] TMPRSS2 is stechiometrically contiguous to ACE2 receptor. [10] The cleavage of the viral protein by TMPRSS2 is a crucial step because, after S1 detachment, the remaining viral S2unit undergoes a conformational rearrangement which drives and completes the fusion between the viral and cellular membrane, with subsequent entry of the virus into cell, release of its content, replication, and infection of other cells. The importance of TMPSRR2 is supported by the evidence that entry of SARS-CoV and SARS-CoV-2 into cells is partially blocked by camostat mesylate, an inhibitor of TMPSRR2.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167588/
Source ReF : https://www.ncbi.nlm.nih.gov