**3. Molecular mechanisms of ACE2 expression during COVID-19**

Angiotensin converting enzyme-2 (ACE2) receptors serve as medium for entry of SARS-CoV-2, the receptor is found attached in the plasma membrane of the cells in the heart, vessels, gut, lung, kidney, testis and brain and very rarely found solubilized in the circulation [19]. The function of ACE2 is to break down Ang II and form Ang 1-7, therefore ACE2 helps in checking the levels of Ang II and plays an important role in renin-angiotensin system (RAS) [20]. It is an established fact now that ACE2 expression is significantly down-regulated during COVID-19 which

#### **Figure 2.**

*Homo-dimerization of ACE2 receptor in case of higher expression levels of ACE2 gene results into decreased interaction and entry of virus into the host cell. BOAT transporter protein makes this process even more difficult, thereby decreasing the levels of viral multiplication.*

results into abnormally increased levels of Ang II, which leaves critical organ systems susceptible to hyper-inflammation and failure [21, 22]. In an unpublished but important paper, it is significantly shown that the homo-dimerization of ACE2 as a result of its higher expression levels prevents binding of Spike protein (S-protein) complex of SARS-CoV-2 virus [23]. This study supports the hypothesis that ACE2 in its monomeric form, can bind to S-protein of the virus with greater preference. ACE2 acting as e-QTLs (Expression quantitative trait loci) due to natural genetic variations it results into homo-dimerized forms which lead to lowered cleavage by TMPRSS2 (**Figure 2**). The presence of broad neutral amino acid transporter, B0AT1 make the completion of this step even more difficult implied by the virus to get into the host cell. It is identified that natural variations in host genes like ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3 might help in bringing such homo-dimerizing structural variations in ACE2.
