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Location and Purpose of ACE 2.

Given that the primary purpose of the transmembrane enzyme ACE 2 is ostensibly to bind Angiotensin 1 and 2 in order to convert these to derivatives such as Angiotensin [1-7] in the case of AT2, and presuming that this function requires its expression in the endothelial cell membrane on the vascular side of pulmonary alveolar structures and indeed vascular endothelium generally (since Angiotensin 1 and 2 are circulating proteins), then what is its supposed purpose in the membranes of type 2 pneumocytes on the exterior side of alveolar epithelium where, if the presumption is correct, it does not bind AT2, and where it is peculiarly susceptible to destructive binding of the S1 spike protein of the SARS-CoV2 virus?

In the absence of a plausible explanation for that location of ACE 2, it might be possible, for example, to speculate rationally that part of that purpose, teleologically as it were, is in fact to bind that spike protein, in which case one is emboldened to inquire upon a broader evolutionary intention in such a relation between that virus and the human organism, and on the nature of that relation generally.

Part of this inquiry then requires further consideration of the extent to which ACE 2 receptors on the luminal side of vascular endothelium locally in the cardio-pulmonary vasculature and more generally are then implicated in the dissemination of the virus. Part of this question involves the likelihood that some auto-immunity mediated by cytotoxic T-cells primed by mRNA vaccines to target the S1 spike protein might develop against AT2 itself by virtue of this common affinity for ACE 2; notwithstanding that such an effect has not been demonstrated in clinical trials of such vaccines to date.

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  • $\begingroup$ I think you will find that just because a particular protein function is required at a particular surface of a cell, it doesn't mean that it is not also found on other cell surfaces... $\endgroup$
    – bob1
    Aug 6, 2021 at 19:26
  • $\begingroup$ @bob 1.. Yes, you may be correct; but truly, what is it doing there? In this case, if the assumption is correct about the definitive function of ACE 2, then the very fact that it is also susceptible to destructive binding by the spike protein should militate against its persistence at such a site, just swinging in the breeze so to say; implying a real evolutionary disadvantage unless some higher consideration is afforded to the role of the coronavirus. Of course, this requires a view of nature in general as precise and ruthlessly exacting with respect to intention, whatever that may be. $\endgroup$
    – jeremiah
    Aug 7, 2021 at 15:02
  • $\begingroup$ Almost all proteins are multifunctional, ACE-2 has functions in brain biochemistry, inflammation and immunology, cardiovascular... try this paper for basic information $\endgroup$
    – bob1
    Aug 8, 2021 at 10:16
  • $\begingroup$ @bob 1. Yes, I've read that paper. All those functions of ACE 2 you mention pertain to its effects on AT2 and AT1. The issue though is not whether ACE 2 is multifunctional, which no doubt it is, but what its function is on the alveolar side of the pneumocyte membrane where, since it is unlikely to exercise the specific function of binding and modifying AT2, its role is in question. This is not an idle or inconsequential question since it is not outlandish to argue that at least part of its function there may be specifically to bind the SARS-CoV 2, and possibly other coronaviruses; therefore.. $\endgroup$
    – jeremiah
    Aug 8, 2021 at 16:01
  • $\begingroup$ ... therefore to imagine some useful function for these viruses -- indeed for viruses generally -- within the dynamic of human evolution. Since this line of thought no doubt requires a challenging philosophical perspective upon reality which may or may not be valid, I would rather find some more concrete and immediate purpose for the ACE 2 at that alveolar site -- which is really why the question is asked. Bear in mind too that until a few years ago, very little was known about ACE 2, and not much more now. $\endgroup$
    – jeremiah
    Aug 8, 2021 at 16:09

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After some fruitful discussion in Comments with 'bob 1', and a review of several articles cited below, the likely answer to the question is that, in spite of the fact that ACE 2 expressed on the atmospheric side of type 2 epithelial pneumocytes cannot in the ordinary circumstance be exposed to circulating Angiotensin [1 or 2], its expression and activity appears to be strongly protective of lung tissue in conditions of inflammation or infection, as these two excerpts attest. Whether this is due to the mitigating effect of ACE 2 during cell rupture or leakage of Angiotensin 2 into the interstitium or alveolar space is unclear, but would seem likely.

At the same time, as mentioned in the following, the fact that ACE2 has two distinct binding sites at this level suggests that its role is not restricted to that protective function generally; rather, more specifically its very presence as a portal with an allied tissue protective function presumably serves to mitigate the inflammatory effect of binding by SARS-CoViruses themselves, 1 and 2, notwithstanding the destructive effect on ACE2 of that process. This interplay between ACE2 expression and viral load/virulence may help to explain the widely varying clinical impact of COVID-19.

Article 3 further below suggests the manner in which such an interaction between host and virus would have evolved.

[a] Article 1 entitled' ACE 2: SARS-CoV 2 Receptor and Regulator of RAS' (Gheblawi etal.).

Lung epithelial cells express high levels of ACE2, which positively correlates with airway epithelial differentiation. Involvement of ACE2 in Acute Respiratory Distress Syndrome [ARDS], which is triggered by multiple diseases including SARS-CoV and SARS-CoV-2, has been established in multiple animal models. ACE2 Knocked-Out mice exhibit severe pathology of ARDS.

Additional ACE deficiency, or treatment with AR1R blockers of ACE2 KO mice rescues them from ARDS implicating the benefit of ACE2 and the critical balance of the protective versus pro-inflammatory and fibrotic axes of the Renin-Angiotensin System [RAS]. These findings are consistent with evidence of a beneficial effect of rhACE2 on pulmonary blood flow and oxygenation in a pig model of lipopolysaccharide-induced ARDS. Age-related loss of ACE2 in the lungs correlates with the increased mortality and worsened phenotype in elderly patients with COVID-19.


[b] Direct Protective Actions of ACE2 on Lung Alveolar Epithelial Cells 2 [Article, 'ACE 2, Much More Than Just a Receptor for SARS-CoV2'].

In addition to its protective role in the cardiovascular system, ACE2 has a direct protective role in alveolar epithelial cells. In the lungs ACE2 has numerous physiological functions, most of which are protective against lung injury. Similar to the endothelial site, ACE2 degrades the octapeptide Ang II by removing a single amino acid from the C-terminal end of the peptide to generate the heptapeptide Ang1-7.

Our laboratory and others have shown that ACE2 protects against lung injury by: (a) degrading Ang II, which is vasoconstrictive and proapoptotic for lung epithelial cells (Wang et al., 1999) and profibrotic (Li et al., 2008; Uhal et al., 2011), and (b) by producing the peptide Ang1-7, which inhibits the actions of Ang II through binding to the MAS receptor (Gopallawa and Uhal, 2014).

In support of this protective role for ACE2, pharmaceutical preparations of recombinant ACE2, when administered to experimental animals, protect against lung cell death, inhibit acute lung injury and prevent lung fibrosis after chronic injury to the lungs (Li et al., 2008; Rey-Parra et al., 2012).

As further evidence, the application of a specific competitive inhibitor of ACE2, DX600, to primary cultures of isolated ACEs increases the level of Ang II released into the serum-free culture medium by autocrine mechanisms, reduces the amount of released Ang1-7 and, importantly, induces apoptosis inhibitable by the AT1 receptor blocker (Menter et al., 2020). Thus, functional ACE2 normally expressed by alveolar epithelial cells can be viewed as a critical survival factor for these lung cells. In addition, the enzymatic product of ACE2, the Ang1-7, itself protects against lung cells death by antagonizing that actions of Ang II (le Tran and Forster, 1997).

If Ang1-7 is applied to cultures of lung epithelial cells, it can prevent lung cell death in response to either Ang II or the ER stress inducer MG132 (Nguyen and Uhal, 2016). The Ang1-7 receptor MAS and the JNK-selective phosphatase MKP-2 appear to be critical in this protective action of Ang1-7 response, because iRNAs or antisense knockdowns of MAS or MKP-2 can eliminate the ability of Ang1-7 to prevent lung cell death (Gopallawa and Uhal, 2016). Indeed, Ang1-7 itself and congeners of the peptide, such as cyclic Ang1-7 (Gopallawa and Uhal, 2016), have already been shown to protect the lungs in preclinical models of acute lung injury.


However, the not unrelated possibility also remains that since there are two distinct binding sites on the ACE2 found in these alveolar epithelial cells, one of which is the catalytic site implicated in its modifying effects on Angiotensin, and the other, the N-terminal protease domain which specifically binds the spike protein of coronaviruses, SARS-CoV2 in particular, at least part of the role of this binding domain has persisted for the purpose of facilitating entry of coronaviruses, more especially with as little immediate inflammatory damage to the portal as possible.

From the same article mentioned 1, the key observation is as follows;

ACE2 has an extracellular facing N-terminal domain and a C-terminal transmembrane domain with a cytosolic tail. The N-terminal portion of the protein contains the claw-like protease domain (PD), while the C-terminal domain is referred to as the Collectrin-like domain. The receptor-binding domain (RBD) of SARS-CoV-2 binds with the PD of ACE2, forming the RBD-PD complex distinct from the ACE2 catalytic site.


This observation may suggest a type of evolutionary symbiosis between coronaviruses generally, SARS-CoV2 in particular, and the human organism which has adapted to permit the entry of those viruses via the N-terminal protease domain which is evidently distinct from the ACE2 catalytic site. Naturally this sort of speculation presupposes that the role of this protease is not restricted to some ordinary physiological function, such as enhancing reabsorption of surfactant by alveolar macrophages for example.

Here it may be interesting to insert an excerpt from another article 3 from 2012 quoted below and dealing with the original SARS-CoV.

Article 3, 'Evidence for ACE2-Utilising Coronaviruses in SARS in Bats'.

In 2002, severe acute respiratory syndrome (SARS)-coronavirus (CoV) appeared as a novel human virus with high similarity to bat coronaviruses. However, while SARS-CoV uses the human angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry, no coronavirus isolated from bats appears to use ACE2. Here we show that signatures of recurrent positive selection in the bat ACE2 gene map almost perfectly to known SARS-CoV interaction surfaces. Our data indicate that ACE2 utilization preceded the emergence of SARS-CoV-like viruses from bats.

Cell-surface receptors often play a key role in defining viral host range. New diseases can emerge when existing viruses evolve the ability to bind the ortholog of their cell-surface receptor in a new species. Indeed, the principal genetic component defining host range in coronaviruses is the spike protein on the surface of the virus and, in particular, its receptor-binding domain (RBD).

It is believed that the severe acute respiratory syndrome (SARS) epidemic resulted from the zoonotic transmission of a coronavirus from bats to humans. The central role of the RBD in the SARS-coronavirus (CoV) zoonosis was crystallized in an experiment in which a bat coronavirus became infectious in primate cells when it was altered to contain the RBD of human SARS-CoV.

Over long periods of time, co-evolutionary dynamics can develop between viruses and their hosts. For example, host populations will experience natural selection for receptor mutations that reduce virus interaction affinity, and viruses will, in turn, be selected for mutations that increase affinity with new receptor variants. This back-and-forth selection will result in the rapid evolution of both the host receptor and the virus surface protein.

The protein evolutionary rate can be analyzed by studying the rates of accumulation of non-synonymous (dN; changing the encoded amino acid) and synonymous (dS; silent) mutations in the underlying gene. Most genes retain far fewer non-synonymous mutations than synonymous mutations (dN/dS ≪ 1) because protein-altering mutations tend to be deleterious.


These are some further pertinent extracts from the article 1 by M. Gheblawi etal. entitled 'ACE 2: SARS-CoV 2 Receptor and Regulator of RAS'.

Knowledge of the underlying biology and physiology of ACE2 (angiotensin-converting enzyme 2) has accumulated over the last 20 years since its discovery and has provided a major stimulus to further our understanding of the renin-angiotensin system (RAS). ACE2 has distinct roles ranging from catalytic activities with various substrates, as functional receptors for severe acute respiratory syndrome coronaviruses (SARS-CoV), and as an amino acid transporter. ACE2 functions as a master regulator of the RAS mainly by converting Ang (angiotensin) I and Ang II into Ang 1–9 and Ang 1–7, respectively.

Whereas somatic ACE contains 2 active sites, ACE2 possesses only a single catalytic domain. Both ACE and ACE2 act as zinc metallopeptidases but of differing substrate specificities defining their distinct and counterbalancing roles in the RAS. Whereas ACE cleaves C-terminal dipeptide residues from susceptible substrates (a peptidyl dipeptidase), ACE2 acts as a simple carboxypeptidase able to hydrolyze Ang I, forming Ang 1–9 and Ang II to Ang 1–7.

ACE2 does not cleave bradykinin, further distinguishing its specificity from that of ACE while it is also insensitive to conventional ACE inhibitors. The C-terminal domain of ACE2, which has no similarity with ACE, is a homolog of a renal protein, collectrin, which regulates the trafficking of amino acid transporters to the cell surface, endowing ACE2 with multiple and distinctive physiological functions. It is the multiplicity of physiological roles that ACE2 plays that has allowed it to be hijacked by SARS-CoV-2 as a receptor.

ACE2 is expressed in the vascular system (endothelial cells, migratory angiogenic cells, and vascular smooth muscle cells), heart (cardiac fibroblasts, cardiomyocytes, endothelial cells, pericytes, and epicardial adipose cells) and kidneys (glomerular endothelial cells, podocytes and proximal tubule epithelial cells). ACE2 is also expressed and functions in the local RAS of the liver (cholangiocytes and hepatocytes), retina (pigmented epithelial cells, rod and cone photoreceptor cells and Müller glial cells), enterocytes of the intestines, circumventricular organs of the central nervous system, upper airway (goblet and ciliated epithelial cells), and alveolar (Type II) epithelial cells of the lungs and pulmonary vasculature.

The entry of both SARS-CoV and SARS-CoV-2 into cells is facilitated by the interaction between viral S-protein with extracellular domains of the transmembrane ACE2 proteins, followed by subsequent down-regulation of surface ACE2 expression.


From the same article, the following details of intestinal expression of ACE 2 may or may not suggest a similar role in pulmonary epithelium.

ACE2 As a Chaperone Protein for the Amino Acid Transporter, B0AT1 (SLC6A19).

B0AT1 is highly expressed in the intestines and kidneys with function in the absorption of neutral amino acids. The ACE2-B(0)AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homo-dimerization. ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the gut microbiome. ACE2 is necessary for the expression of the Hartnup transporter in the intestine, and the differential functional association of mutant B(0)AT1 transporters with ACE2 in the intestine regulates the phenotypic heterogeneity of human Hartnup disorder.


Evidently ACE2 facing the gut lumen also serves to inhibit dysbiosis, and although it is considered unlikely by researchers to exert any corresponding function in the generally aseptic lower respiratory tract, it may play some such role in the upper tract. Altogether, it is an extremely interesting enzyme, a zinc metallo-enzyme no less, whose importance is yet to be fully appreciated.


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  • $\begingroup$ Nice synthesis of the current research. Looks like it could be an interesting PhD topic for someone. BTW, you might want to format the excerpts as blockquotes to make it more clear which bits are from papers and your comments. $\endgroup$
    – bob1
    Aug 9, 2021 at 22:29

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