- subcellular expression
- tissue and organ expression
- mediators that influence expression
- comparing to TMPRSS2 expression
- circulating expression
- expression in embryonic development

ACE2 Expression

Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

ACE2 variants and COVID-19

ACE2 is located on the X chromosome (Xp22), and belongs to a subset of genes that escapes X-inactivation, showing a heterogenous sex bias and evolutionary characteristics of tissue specificity and expression (Tukiainen et. al). However, expression differences in distinct tissues suggest presence of X-inactivation, though incomplete.

The figure below shows ACE2 preferential expression in males (blue). 

Smith College

State University of New York at Stony Brook

ACE2 is a homologue of ACE.  Both enzymes are carboxypeptidases, meaning they cleave amino acids from the c-terminal of the peptide.  However, these homologues cleave the amino acid sequences at different points which leads to their different products.  ACE2 has four main physiological roles:

- Regulating blood pressure via its role in the renin-angiotensin-aldosterone system (RAAS)

- Limiting the amount of ACE substrate by converting Ang I into Ang 1-9

- Degrading Ang II in order to minimize its harmful effects

- Forming Ang 1-7 in order to maximize its cardioprotective effects

Angiotensin-converting enzyme 2 (ACE2)

X-chromosome inactivation (XCI) has been shown to be incomplete in humans, with around one third of genes being expressed in both active (Xa) and inactive (Xi) chromosomes. Approximately 23% of the X-chromosomal genes are affected by XCI incompleteness.

Some escape genes (n > 60) have shown enriched, sex-biased expression.

Escape Genes

Benetti, E., Tita, R., Spiga, O. et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur J Hum Genet (2020). doi: 10.1038/s41431-020-0691-z https://www.nature.com/articles/s41431-020-0691-z#citeas

ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Tukiainen, T., Villani, A. C., Yen, A., Rivas, M. A., Marshall, J. L., Satija, R., ... & Cummings, B. B. (2017). Landscape of X chromosome inactivation across human tissues. Nature, 550(7675), 244-248. doi:10.1038/nature24265. https://www.nature.com/articles/nature24265

Landscape of X chromosome inactivation across human tissues

Xiao, L., Sakagami, H., & Miwa, N. (2020). ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?. Viruses, 12(5), 491.
doi: 10.3390/v12050491

ACE2: The Key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

The nine amino acid long peptide that is formed when ACE 2 acts on Ang 1.  Ang 1-9 and Ang 1-7 are negative regulators of RAS.  

Ang 1-9

The seven amino acid long pepetide that is formed when ACE 2 acts on Ang II.  Ang 1-9 and Ang 1-7 are negative regulators of RAS.  Ang 1-7 is biologically active with MasR being its receptor.  This molecule alleviates the effects of Ang II/AT1R and has cardioprotective properties.  

Ang 1-7

- Inhibition of the binding between the spike protein present on the surface of the virus and the ACE-2 receptor present in the membrane of the host cell. This interaction mediates the entry of the virus in the cell. 
- Because ACE 2 plays a central role in the pathogenesis of COVID-19, it is thought that it could be an efficient drug target that could either treat or prevent infection. 

ACE2 normal role:
-Critical to regulate processes such as pressure, wound healing, and inflammation. 


-It helps modulate ANGII, a protein that increases blood pressure and inflammation, increasing damage to blood vessel lining and tissue. 

COVID-19:
-In response to COVID-19, ANGII has increased inflammation and the death of alveoli cells which are critical for bringing oxygen into the body...ACE2 prevents this.

-When COVID-19 virus binds to ACE2, it inhibits its action, thus increasing the effects of ANGII
 

ACE 2 Receptor as a Pharmacological Target for Treating or Preventing COVID-19

This virus uses angiotensin-converting enzyme 2 (ACE2) as a functional cellular receptor.
The virus also binds to the C-type lectin CD209L (also known as L-SIGN) and DC-SIGN

SARS-CoV cellular receptor

Three primary observations have been made about ACE2 and its relation to SARS/COVID-19:

- ACE2 acts as a functional receptor for SARS-CoV-2 to enter host cells
- Increased ACE2 expression may elevate the risk of a SARS-CoV-2 infection as well as the development of COVID-19
- Reduced ACE2 expression may lead to acute respiratory distress syndrome

SARS‐CoV‐2 may be able to infect other tissues that express ACE2 using viral RNA that circulates in the blood.  

ACE2 in the Pathogenesis of COVID-19

ACE2 Chromosomal Localization and Activation.

Intestinal ACE2 controls the expression of anti-microbial peptides (AMPs) and regulates intestinal homeostasis through its role in dietary amino acid uptake.  A lack of tryptophan, specifically, is thought to lead to adverse effects as it and its metabolites influence microbial ecology, microbial metabolism, and the interaction between the microbiota and its host.  Animal studies have shown that ACE2 knock outs had altered gut microbiotas, decreased AMP expression, and impaired amino acid uptake.  

ACE2 Modulates Gut Microbiota Composition

ACE2 structure components:
- signal peptide
- single metalloprotease active site
- transmembrane domain

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