A Bioinformatics-Based Study of
Angiotensin I Converting Enzyme 2 (ACE2) in Homo sapiens
​
Jeffrey Joseph and James Martinez
Published: December 17, 2020
DISCUSSION
The purpose of this project was to utilize bioinformatics methods to identify a protein from a partial amino acid sequence, and then perform an in depth analysis of the protein and the gene that the protein is encoded by. This project makes use of common bioinformatics databases and tools to identify key features on small and large scales regarding the specific gene and protein.
The Gene
Isoform I of the Angiotensin I Converting Enzyme II (ACE2) was the protein that was found to be encoded by the ACE2 gene. The ACE2 gene is 83,962 base pairs long and contains 21 distinct exons and 20 introns. A total of 12 mRNA variants were found that encoded for 4 isoforms of ACE2. Specifically, isoform 1 and 4 were mainly studied with variant 2 coding for isoform 1 and variant 5 coding for isoform 4. The 3’ UTR was the same length for variant 2 and 5, however both differed in their 5’ UTR lengths. A huge takeaway from this analysis was that variant 2 had a complete set of nucleotides encoding for ACE2’s functional metallopeptidase domain, whereas variant 5 had an incomplete set, thus causing isoform 4 to not express the appropriate metallopeptidase functioning. The lack of the functional domain, as backed by recently published studies, is integral for prevention of SARS-CoV-2 binding. Hence, this makes the Variant 5 interferon an inducible promoter region for possible targets for disease prevention.
Protein Structure
ACE2 is a protein that is being actively studied today. Databases such as Protein Data Bank (PDB) and Refseq show several molecular models of ACE2 binded to other proteins such as SARS-CoV-2 spike protein or to Angiotensin II. A majority of models created are based on complexes ACE2 can form rather than just the native protein itself. UniProt was one of the few databases that was able to provide a single structure of ACE2. Isoform 1 of ACE2 is made up of 805 amino acids. It is composed of two domains: the zinc metallopeptidase and collectrin. The zinc metallopeptidase domain is where catalysis occurs and is the location at which substrates bind to. The collectrin domain mainly serves to stabilize ACE2 in the transmembrane of a cell.
Protein Function
The top function of ACE2 that was revealed through this research is that ACE2 cleaves specific amino acids off of certain polypeptides. ACE2’s main function is that it conducts carboxypeptidase activity, which involves cleaving an amino acid residue from the C-terminal end. An important role that ACE2 plays with this function is conducting cleavage and converting angiotensin I into angiotensin (1-9) or angiotensin II into angiotensin (1-7) in the Renin-Angiotensin-Aldosterone System. The ACE2 protein also serves as a receptor for the SARS-CoV-2 virus, which is a hot topic in research today. Primarily, ACE2 was associated with the Renin-Angiotensin-Aldosterone System in regulating blood pressure, however it is also associated with virus binding activity. ACE2 is expressed in many tissues of the body, but primarily in the lungs, heart, small intestine, testis, and kidneys. Currently, the different isoforms of ACE2 are still being studied, but evidence of isoform 1 and 4 expression are the most well known.
Mutations and Disease Association
It is well known that ACE2 is involved with hypertensive related diseases and the Sars-Cov-2 virus. Hypertension occurs when a high force of blood is exerted on the walls of the arteries. This high force is mainly due to constriction of the artery walls caused by the peptide hormone angiotensin II. Thus, ACE2 is essential for converting angiotensin II into angiotensin (1-7), which helps to lower the force of exertion or blood pressure. If the expression of ACE2 is downregulated in high folds, hypertension can ensue, leading to determinants such as heart failure and kidney damage.
​
ACE2’s binding domain is projected towards the extracellular space, which makes ACE2 prone to its binding with the Sars-Cov-2 virus. It is evident that this binding of the Sars-Cov-2 virus to the ACE2 receptor is highly prevalent and can lead to several, quick detriments to the body such as fever and loss of senses. Clinical studies are continuously being conducted in order to study the relationship between ACE2 and Sars-Cov-2 today.
CONCLUSION
Overall, this project helped us to learn about the ACE2 receptor and the implications that it has on the world today. This project gave us the opportunity to apply the knowledge we learned in class and continue further research through the use of bioinformatics tools and databases. This project revealed to us the beneficial power that bioinformatics has in the world today, especially by providing information in an instant.