Angiotensin-Converting Enzyme 2 (ACE2) is a highly specialized protein that acts as a biological catalyst, regulating various physiological functions within the body’s internal control systems. Understanding the function of this enzyme is important for grasping how the body maintains balance and for comprehending the mechanisms behind recent global health challenges.
Defining Angiotensin-Converting Enzyme 2
Angiotensin-Converting Enzyme 2 (ACE2) is a protein that exists primarily as a membrane-bound molecule, anchored to the surface of many different cell types throughout the body. Structurally, it is classified as a metallopeptidase, meaning it requires a metal ion, specifically zinc, to perform its catalytic function. This enzyme belongs to a family that includes its homolog, Angiotensin-Converting Enzyme (ACE), often called ACE1. While both enzymes process peptide hormones, their actions create a counter-regulatory balance.
ACE1 primarily functions to cleave the hormone Angiotensin I, converting it into the active molecule Angiotensin II. Angiotensin II is a potent peptide that causes blood vessels to constrict, raising blood pressure. In contrast, ACE2 acts as a negative regulator by specifically breaking down Angiotensin II. This action produces a smaller, protective molecule known as Angiotensin (1-7), which has opposing effects in the body.
ACE2 functions as a carboxypeptidase, removing a single amino acid from the C-terminus of its substrates. This specific catalytic activity transforms the constricting and inflammatory effects of Angiotensin II into the dilating and protective effects of Angiotensin (1-7). This chemical distinction establishes ACE2 as a regulatory checkpoint, modulating the overall activity of a complex system of hormones.
Essential Role in Systemic Regulation
The primary role of ACE2 is to govern the Renin-Angiotensin System (RAS), a complex hormonal network that manages blood pressure, fluid balance, and inflammation across multiple organs. Within the RAS, Angiotensin II, generated by ACE1, acts to increase vascular tone and promote processes that can lead to tissue damage. This pathway is often referred to as the classical axis of the RAS.
ACE2 operates as the protective arm of this system, working to balance the potent effects of Angiotensin II. By metabolizing Angiotensin II into Angiotensin (1-7), ACE2 shifts the body’s physiological response toward relaxation and repair. Angiotensin (1-7) signals through a different receptor, known as MasR, to trigger beneficial effects.
The downstream effects of this ACE2-driven pathway include vasodilation, the widening of blood vessels, which helps lower systemic blood pressure. Angiotensin (1-7) also has anti-inflammatory and anti-fibrotic properties, helping prevent excessive scarring of tissues. This protective function is particularly important in organs that are highly vascularized and prone to stress.
High expression of ACE2 is observed in the heart, kidneys, and lungs, highlighting its widespread involvement in cardiovascular and respiratory health. In the heart, its activity protects against muscle hypertrophy and remodeling, which can lead to heart failure. In the lungs, ACE2’s presence helps to maintain the delicate balance of the RAS necessary to prevent acute lung injury. The enzyme thus serves as a natural defense mechanism against over-activation of the body’s own pressure-regulating hormones.
The Gateway: ACE2 as the SARS-CoV-2 Receptor
ACE2 gained widespread recognition because it functions as the primary cellular entry point for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. The virus uses its prominent spike protein to physically attach to the ACE2 enzyme on the surface of human cells. This interaction is highly specific, similar to a lock-and-key mechanism, which is necessary for the virus to initiate infection.
Once the viral spike protein binds to ACE2, other host enzymes on the cell surface help to process the spike protein, enabling the fusion of the viral and cellular membranes. This process allows the genetic material of the virus to enter the cell and begin replication. The efficiency of this binding determines the infectious potential of the virus in humans.
The distribution of ACE2 across different organs helps to explain the varied and systemic symptoms of COVID-19. High concentrations of ACE2 are found on the surface of type II pneumocytes, which are cells in the lungs responsible for producing surfactant. This abundance explains why the lungs are the primary site of severe respiratory disease.
Additionally, ACE2 is present in cells lining the heart, kidneys, and the gastrointestinal tract, allowing the virus to infect multiple organ systems. A concerning consequence of viral binding is the “downregulation” of ACE2; as the virus enters the cell, it causes the ACE2 enzyme to be internalized or shed from the cell surface. This loss of functional ACE2 prevents it from performing its normal protective role of converting Angiotensin II to Angiotensin (1-7). The resulting imbalance leads to an unchecked buildup of Angiotensin II, which can exacerbate inflammation, promote fluid accumulation in the lungs, and contribute to acute lung injury.
Therapeutic Relevance and Future Research
The dual role of ACE2—as a protective enzyme and a viral gateway—has made it a significant focus for the development of new treatments. One promising strategy involves using a molecule called recombinant human soluble ACE2 (rhACE2). This engineered protein is essentially a free-floating version of the enzyme that lacks the membrane anchor, allowing it to circulate in the bloodstream.
When administered, rhACE2 acts as a “decoy receptor,” binding to the viral spike protein and neutralizing the virus before it can attach to the ACE2 on a patient’s own cells. Simultaneously, this soluble form of the enzyme retains its ability to convert Angiotensin II into the protective Angiotensin (1-7). This dual action offers the potential to both block viral entry and restore the body’s natural defense against tissue damage.
Research is also exploring ways to enhance ACE2’s protective function for conditions unrelated to viral infection, such as heart disease and kidney issues. Scientists are investigating drugs that could selectively increase ACE2 expression or activity to provide greater cardioprotection and reduce fibrosis. Separately, patients taking common blood pressure medications, specifically ACE inhibitors and Angiotensin Receptor Blockers (ARBs), have been advised to continue their treatment. Although these drugs can indirectly affect ACE2 levels, major health organizations have determined that the benefits of maintaining treatment for cardiovascular health outweigh any theoretical risks related to viral infection.