Angiotensin-converting enzyme 2, commonly known as ACE2, is a protein found on the surface of many human cells. It functions as an enzyme, meaning it facilitates biochemical reactions within the body. Specifically, ACE2 can break down larger proteins into smaller components that then influence various cellular activities. This protein acts as a receptor, serving as an entry point for certain viruses to access and infect human cells.
Location and Structure of ACE2
ACE2 receptors are widely distributed throughout the human body. They are found extensively on epithelial cells, which form protective barriers in various tissues. High concentrations of ACE2 are present in the lungs, particularly on type 2 pneumocytes within the alveoli, where gas exchange occurs.
ACE2 receptors are also abundant in several key organs and cell types:
The heart, including epicardial, adipocyte, fibroblast, myocyte, and coronary artery cells.
The kidneys (tubular epithelial cells) and intestines (epithelial cells).
Endothelial and smooth muscle cells of blood vessels.
The brain and testes.
Structurally, ACE2 is a single-pass type I transmembrane protein composed of 805 amino acids. It has an extracellular domain containing a zinc metallopeptidase catalytic site, which is the enzymatically active part exposed on the cell surface. This extracellular domain also includes the binding site for certain viral spike proteins. The protein also features a C-terminal transmembrane anchor that secures it within the cell membrane and a short C-terminal domain facing the cell’s interior.
Physiological Functions of ACE2
ACE2 plays a role in the renin-angiotensin system (RAS). This system regulates blood pressure, fluid balance, and various organ functions. Within the RAS, ACE2 acts as a counter-regulatory enzyme to Angiotensin-Converting Enzyme (ACE), which produces angiotensin II (Ang II).
Ang II is a peptide hormone that causes blood vessels to constrict, increasing blood pressure and promoting inflammation and tissue damage. ACE2 converts Ang II into angiotensin (1-7), a peptide that has opposing effects, such as relaxing blood vessels and reducing inflammation. This conversion helps to lower blood pressure and protect organs like the heart, lungs, and kidneys from the harmful effects of excessive Ang II.
Beyond its role in blood pressure regulation, ACE2 also contributes to other cellular processes. It is involved in the transport of neutral amino acids in the gut and kidneys. This function is linked to amino acid homeostasis and has implications for conditions like Hartnup’s disease. ACE2 also exhibits protective effects against inflammation and fibrosis in various tissues, contributing to overall organ health.
ACE2 and Viral Entry
ACE2 serves as the primary gateway for certain viruses, including SARS-CoV (the virus that caused the 2003 SARS outbreak) and SARS-CoV-2 (the virus responsible for COVID-19), to enter human cells. The entry process begins with the virus’s spike (S) protein, which protrudes from the viral surface. The spike protein contains a specific region called the receptor-binding domain (RBD).
This RBD acts like a “key” that specifically recognizes and binds to the ACE2 receptor on the host cell surface, which functions as the “lock”. After binding, host cellular proteases, such as TMPRSS2, cleave and activate the viral spike protein. This cleavage induces structural changes in the spike protein, facilitating the fusion of the viral membrane with the host cell membrane.
Once the viral and host cell membranes fuse, the genetic material of the virus enters the host cell’s cytoplasm. Inside the cell, the virus hijacks the host cell’s machinery to replicate. This replication leads to infection, cellular damage, and disease symptoms. The high affinity of SARS-CoV-2’s spike protein for human ACE2 contributes to its efficient cell entry and widespread infectivity.
Therapeutic and Research Insights
Understanding ACE2 receptors has opened avenues for scientific research and therapeutic strategies. A primary focus involves developing interventions that block the binding of viruses, such as SARS-CoV-2, to ACE2. This aims to prevent viral entry into host cells, mitigating infection and its progression. Researchers are exploring molecules, including antibodies or small-molecule drugs, that could competitively bind to ACE2 or the viral spike protein, acting as decoys.
Another strategy involves modulating ACE2 expression or activity. This could involve increasing ACE2 activity to enhance its protective effects against conditions like lung injury or cardiovascular disease, or reducing its availability to viruses. For instance, a soluble form of ACE2 (sACE2) is being investigated as a “decoy receptor.” This soluble ACE2 can circulate in the bloodstream, bind to viral spike proteins, and prevent them from attaching to cell surfaces, blocking viral entry.
Ongoing research also explores the interplay between ACE2, the renin-angiotensin system, and immune responses. Insights from these studies could lead to therapies that not only target viral entry but also help regulate the body’s inflammatory response to infection. These efforts aim to translate understanding of ACE2 into effective treatments for viral diseases and other conditions where ACE2 plays a role.