Angiotensin-converting enzyme 2 (ACE2)
is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that can be found either attached to the
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
of cells (mACE2) in the
intestines
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
,
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
,
testis
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
,
gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...
, and
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
or in a soluble form (sACE2).
Both membrane bound and soluble ACE2 are integral parts of the
renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. While mACE2 does not appear to factor into the harmful phase of RAAS (the increase of blood pressure), its existence is vital in order for the enzyme ADAM17 to cleave its extracellular domain to create soluble ACE2 (sACE2). Soluble ACE2 lowers blood pressure by catalyzing the
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of
angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
(a
vasoconstrictor
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessel ...
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
) into
angiotensin (1–7) (a
vasodilator
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
)
which in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.
This decrease in blood pressure makes the entire process a promising drug target for treating
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
s.
mACE2 also serves as the entry point into cells for some
coronaviruses
Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the com ...
, including
HCoV-NL63,
SARS-CoV
Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; or Severe acute respiratory syndrome coronavirus, SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for t ...
, and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
.
The SARS-CoV-2 spike protein itself is known to damage the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
via downregulation of ACE2. The human version of the enzyme can be referred to as hACE2.
Structure
Membrane bound Angiotensin-converting enzyme 2 (mACE2) is a zinc-containing
metalloenzyme
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...
located on the surface of intestinal
enterocytes
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its s ...
, renal tubular cells and other cells.
mACE2 protein contains an
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
peptidase M2 domain and a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
collectrin renal
amino acid transporter
An amino acid transporter is a membrane transport protein that transports amino acids. They are mainly of the solute carrier family.
Families
There are several families that function in amino acid transport, some of these include:
TC# 2.A.3- ...
domain.
mACE2 is a single-pass
type I membrane protein
A single-pass membrane protein also known as single-spanning protein or bitopic protein is a transmembrane protein that spans the lipid bilayer only once. These proteins may constitute up to 50% of all transmembrane proteins, depending on the orga ...
, with its enzymatically active
domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
exposed on the surface of cells in the intestines and other tissues.
The extracellular domain of mACE2 can be
cleaved from the
transmembrane domain
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...
by another enzyme known as
ADAM17 a member of the
sheddase
Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface. Many sheddases are members of the ADAM or aspartic protease (BACE) protein families.
The ...
enzyme family, during the protective phase of
RAAS, the Renin Angiotension Aldosterone System which regulates our body's blood pressure. The resulting cleaved protein is known as soluble ACE2 or sACE2. It is released into the bloodstream where one of sACE2's functions is to turn excess angiotensin II into angiotensin 1-7 which binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. Excess sACE2 may ultimately be excreted in the urine.
Location within the human body
mACE2 is attached to the cell membrane of mainly
enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...
s of the
small intestine
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
and
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
,
proximal tubular cells of the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s, glandular cells of the
gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...
, as well as
Sertoli cells
Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimula ...
and
Leydig cells
Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...
of the
testis
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
.
The expression profile of mACE2 in the human body was recently thoroughly evaluated by the
Human Protein Atlas
The Human Protein Atlas (HPA) is a Swedish-based program started in 2003 with the aim to map all the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometr ...
team using a large-scale multiomics approach combining several different methods for analysis of gene expression, including a stringent immunohistochemical analysis using two independent antibodies.
In addition to the above-mentioned issues, mACE2 expression was also seen in
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
and
pericytes
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood c ...
of blood vessels within certain tissues,
cardiomyocytes
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
in heart tissue, and a smaller subset of cells within the
thyroid gland
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes are connected by a thin band of Connective tissue, tissue cal ...
,
epididymis
The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...
,
seminal vesicle
The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.
The vesicles are 5†...
,
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
,
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
and
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
. Despite the fact that the
respiratory system
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
is the primary route of
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
infection, very limited expression is seen, both at protein and mRNA level. The expression within the respiratory system is mainly restricted to the upper bronchial and nasal
epithelia
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
, especially in the
ciliated cells.
Function
As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to the
angiotensin-converting enzyme (ACE). ACE cleaves
angiotensin I
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the a ...
hormone into the vasoconstricting
angiotensin II
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
which causes a cascade of hormonal reactions which is part of the body's harmful phase of RAAS, which ultimately leads to an increase in the body's blood pressure. ACE2 has an opposing effect to ACE, degrading angiotensin II into
angiotensin (1-7)
Angiotensin (1-7) (; Molecular weight = 899.02 g/mol; H- Asp- Arg-Val- Tyr- Ile-His- Pro-OH) is an active heptapeptide of the renin–angiotensin system (RAS).
In 1988, Santos ''et al'' demonstrated that angiotensin (1-7) was a main product of th ...
, thereby lowering blood pressure.
sACE2, as part of RAAS's protective phase, cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator
angiotensin (1-7)
Angiotensin (1-7) (; Molecular weight = 899.02 g/mol; H- Asp- Arg-Val- Tyr- Ile-His- Pro-OH) is an active heptapeptide of the renin–angiotensin system (RAS).
In 1988, Santos ''et al'' demonstrated that angiotensin (1-7) was a main product of th ...
(H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure.
sACE2 can also cleave numerous peptides, including ,
apelin
Apelin (also known as APLN) is a peptide that in humans is encoded by the ''APLN'' gene. Apelin is one of two endogenous ligands for the G-protein-coupled APJ receptor that is expressed at the surface of some cell types. It is widely expressed ...
,
neurotensin
Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine h ...
,
dynorphin A
Dynorphin A is a dynorphin, an endogenous opioid peptide with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys.
Dynorphin A1–8 is a truncated form of dynorphin A with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Ar ...
, and
ghrelin
Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highe ...
.
mACE2 also regulates the membrane trafficking of the neutral amino acid transporter
SLC6A19
Sodium-dependent neutral amino acid transporter B(0)AT1 is a protein that in humans is encoded by the ''SLC6A19'' gene.
Function
SLC6A19 is a system B(0) transporter that mediates epithelial resorption of neutral amino acids across the apica ...
and has been implicated in
Hartnup's disease
Hartnup disease (also known as "pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into sero ...
.
Research in mice has shown that ACE2 (whether it is the membrane bound version or soluble is inconclusive) is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed.
Coronavirus entry point
As a transmembrane protein, mACE2 serves as the main entry point into cells for some
coronavirus
Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the com ...
es, including
HCoV-NL63,
SARS-CoV
Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; or Severe acute respiratory syndrome coronavirus, SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for t ...
(the
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
that causes
SARS
Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first identified strain of the SARS coronavirus species, ''sever ...
),
and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
(the virus that causes
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
).
More specifically, the binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of mACE2 on the surface of cells results in
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
and
translocation of both the virus and the enzyme into
endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s located within cells.
The binding of the SARS-CoV-2 virus through mACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In a study done during the SARS outbreak, SARS virus RNA was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS. It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals. This entry process also requires priming of the S protein by the host serine protease
TMPRSS2
Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the ''TMPRSS2'' gene. It belongs to the TMPRSS family of proteins, whose members are transmembrane proteins which have a serine protease activity. The TMPRSS2 protein is f ...
, the inhibition of which is under current investigation as a potential therapeutic.
It has also been shown that disruption of S-protein
glycosylation
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...
significantly impairs viral entry, indicating the importance of
glycan-protein interactions
Glycan-Protein interactions represent a class of biomolecular interactions that occur between free or protein-bound glycans and their cognate binding partners. Intramolecular glycan-protein (protein-glycan) interactions occur between glycans and ...
in the process.
This has led some to hypothesize that decreasing the levels of mACE2, in cells, might help in fighting the infection. Furthermore, according to studies conducted on
mice
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
, the interaction of the spike protein of the coronavirus with mACE2 induces a drop in the levels of mACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.
On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the
vasodilator
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
angiotensin 1–7.
Furthermore, some researchers have hypothesized that sACE2 (which is created during the Protective Phase of RAAS) is not only involved in binding to Angiotensin II to create Angiotensin I-7 which lowers blood pressure by vasodilation, but that free and soluble ACE2 may also be binding to
coronavirus spike protein
Spike (S) glycoprotein (sometimes also called spike protein, formerly known as E2) is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spike ...
s, hence making those coronavirus spikes unavailable for binding to mACE-2 sites.
But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2 is present.
Both
ACE inhibitor
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
s and
angiotensin II receptor blocker
Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...
s (ARBs) that are used to treat high blood pressure have been shown in rodent studies to upregulate mACE2 expression, possibly affecting the severity of coronavirus infections.
However, a
systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
and
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
published on July 11, 2012, found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." Moreover, "the risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."
An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for patients with hypertension who were taking ACE inhibitors or ARBs. The death rate was compared with 9.8% of hospitalized patients with hypertension not taking such drugs, suggesting that ACE inhibitors and ARBs are not harmful and may help against the coronavirus.
Despite lack of conclusive evidence, some have advocated for and against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.
However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.
Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients, with higher plasma levels being correlated with worse disease outcomes. Patients with high blood pressure or heart disease show elevated ACE2 plasma levels.
Given its role as the SARS-CoV-2 entry receptor, it has been repeatedly hypothesised that population variation in ACE2 may contribute to an individual's
genetic susceptibility
Public health genomics is the use of genomics information to benefit public health. This is visualized as more effective preventive care and disease treatments with better Specificity (statistics), specificity, tailored to the genetic makeup of ea ...
to COVID-19.
Several studies have reported that ACE2
missense variants can alter its
binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
for the Spike protein,
and consequently its susceptibility to SARS-CoV-2 pseudovirus entry,
and there is strong evidence of individuals who carry rare variants in ACE2 that could confer total resistance to SARS-CoV-2 infection.
The expression level of ACE2 at the cell surface is another critical factor affecting viral susceptibility and probably plays a role in the tissue tropism of the virus
and many suspected COVID-19 associated ACE2 variants affect expression.
Recombinant human ACE2
Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for
acute lung injury
Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin color ...
, and appeared to improve pulmonary
blood flow
Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously m ...
and
oxygen saturation
Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen that is dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium at the given temperature. It ca ...
in
piglets with a
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
-induced
acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin colo ...
.
The half-life of rhACE2 in human beings is about 10 hours, and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours.
Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic
renin-angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.
An ''in vitro'' study focused on the early stages of infection found that clinical-grade human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 recovery from
vero cell
Vero cells are a lineage of cells used in cell cultures. The 'Vero' lineage was isolated from kidney epithelial cells extracted from an African green monkey (''Chlorocebus'' sp.; formerly called ''Cercopithecus aethiops'', this group of monkeys ha ...
s by a factor of 1,000-5,000. The equivalent mouse rsACE2 did not have such an effect. This study suggests that rhsACE2 not only restores the renin-angiotensin system to balance as in the earlier ARDS studies, but also directly slows down infection by this virus – possibly as a decoy. ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise the virus ''in vitro''.
An ACE2 triple mutant that displayed nanomolar binding to Spike (sACE2.v2.4),
was later shown to block pseudovirus cell entry in human lung cell lines and prevent SARS-CoV-2 induced ARDS in an ACE2 humanized mouse model.
Infused rhACE2 has been evaluated in clinical trials for the treatment of
acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin colo ...
(ARDS). rhACE2 is in phase II trial for severe COVID-19.
See also
*
Renin–angiotensin system
The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.
When renal blood flow is reduced, juxt ...
*
Angiotensin-converting enzyme
Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstr ...
*
SARS-CoV-2 § Structural biology
References
External links
*
Angiotensin-converting enzyme 2in
Membranome database
Membranome database provides structural and functional information about more than 6000 single-pass (bitopic) transmembrane proteins from ''Homo sapiens'', ''Arabidopsis thaliana'', ''Dictyostelium discoideum'', ''Saccharomyces cerevisiae'', '' ...
3D structureof
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
of a
neurotransmitter sodium symporter B(0)AT1, ACE2, and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
receptor-binding domain in
OPM database
Orientations of Proteins in Membranes (OPM) database provides spatial positions of membrane protein protein structure, structures with respect to the lipid bilayer. Positions of the proteins are calculated using an Implicit solvation, implicit sol ...
*
{{Portal bar, Medicine, Biology
EC 3.4.17
Single-pass transmembrane proteins