Angiotensin converting enzyme 2

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Angiotensin converting enzyme 2
Angiotensin converting enzyme 2
Ribbon model of the human angiotensin converting enzyme 2, according to PDB  1R42
other names
  • ACE-related carboxypeptidase
  • Angiotensin-converting enzyme homolog (ACEH)
  • Metalloprotease MPROT15

Existing structure data : 3SCL , 1R42 , 1R4L , 2AJF , 3D0G , 3D0H , 3D0I , 3KBH , 3SCL , 3SCJ , 3SCK

Properties of human protein
Mass / length primary structure 805 amino acids
Secondary to quaternary structure Heterodimer
Cofactor Zn 2+ , Cl -
Isoforms 2
Identifier
Gene names ACE2  ; ACEH
External IDs
Enzyme classification
EC, category 3.4.17.23 ,  hydrolase
MEROPS M02.006
Response type hydrolysis
Substrate Angiotensin II , angiotensin I.
Products Angiotensin (1-7), angiotensin (1-9)
Occurrence
Homology family CLU_014364_3_0
Parent taxon Eukaryotes , bacteria
Orthologue
human House mouse
Entrez 59272 70008
Ensemble ENSG00000130234 ENSMUSG00000015405
UniProt Q9BYF1 Q8R0I0
Refseq (mRNA) NM_021804 NM_001130513
Refseq (protein) NP_068576 NP_001123985
Gene locus Chr X: 15.56 - 15.6 Mb Chr X: 164.14 - 164.19 Mb
PubMed search 59272 70008

Angiotensin-converting enzyme 2 ( English Angiotensin-converting enzyme 2 , short ACE2 ) is a metallocarboxypeptidase , and a type 1 transmembrane protein with homology to the angiotensin converting enzyme (ACE), which is mainly in eukaryotes , but also in bacteria occurs. ACE2 plays an important role in the renin-angiotensin-aldosterone system (RAAS), which controls the volume balance of the human body and regulates blood pressure .

PCR analyzes showed that ACE2 in heart , and in the lung , kidney , in the endothelium and in the gastrointestinal tract expressed is. Also, ACE2 is a receptor for various coronaviruses , including SARS-CoV and SARS-CoV-2 , to enter cells .

structure

ACE2 contains 20 α-helical segments and nine 3 10 -helices , which together make up about 62% of the structure. In addition, ACE2 has six short β-sheet segments that make up about 3.5% of the structure. The extracellular region of human ACE2 consists of two domains , on the one hand the zinc metallopeptidase domain (also called peptidase domain (PD), position 19-615) and on the other hand the C -terminal collectrin homology domain (or collectrin-like domain) Domain, CLD), which is disordered. The metallopeptidase domain can also be divided into two subdomains (I and II), between which the active center is located. Subdomain I contains the N terminus and the zinc ion and subdomain II contains the C terminus. Both subdomains are connected with an α-helix.

The zinc ion is coordinated in the active center by the amino acid residues His374, His378, Glu402 and a water molecule (in the native state ) . These amino acid residues together form the "HE XX H + E" motif (H = histidine , E = glutamic acid , X = unknown amino acid; see one -letter code ), which is conserved in clan MA in metalloproteases . The chloride ion is coordinated by the residues Arg169, Trp477 and Lys481 in subdomain II.

Subdomains of ACE2.png
Active site of human ACE2.png


Domains of human ACE2: The zinc metallopeptidase domain consists of subdomain I ( red ) and subdomain II ( blue ). The C -terminal collectrin homology domain is shown in green , but only half of it is shown due to the weak electron density map. According to PDB  1R42 .
Active center with “HE XX H + E” motif: The zinc ion ( red ball ) is coordinated by the amino acid residues His374, His378, Glu402 and a water molecule ( blue ball ). Coordinative bonds are shown in magenta .

Physiological function

Protective effect against cardiovascular diseases

ACE2 is a multifunctional enzyme that enhances the vasoconstrictive effects of angiotensin II through the formation of vasodilatory peptides such as angiotensin- (1-7) (also known as Ang- (1-7)) and through the hydrolysis of vasoactive peptides such as apelin-13 , Neurotensin , kinestinin , dynorphin and bradykinin fragments.

Angiotensin II, the main actor in the renin-angiotensin-aldosterone system, binds mainly to the angiotensin II receptor type 1 (AT 1 receptor) and thus causes cell growth , proliferation and migration . In the event of dysregulation, these processes influence the remodeling of the heart and the blood vessel system, which can lead to various cardiovascular diseases . The so-called counter-regulatory axis of the RAAS ( English counter-regulatory axis ) supported by the enzyme and its products ACE2 angiotensin (1-9) proceeds (also Ang- (1-9) known) and angiotensin (1-7) Angiotensin- (1-7) inhibiting the action of angiotensin II by binding to the Mas receptor , plays a protective role in cardiovascular diseases. The cardioprotective effect is partly based on the formation of nitric oxide (NO). Ang- (1-7) stimulates the phosphorylation of endothelial nitric oxide synthase in Mas-expressing cells, among other things via the PI3K / Akt signaling pathway. This activates the synthase and produces nitric oxide.

The binding of angiotensin- (1-9) to the angiotensin II receptor type 2 (AT 2 receptor) in the heart leads to a reduction in collagen synthesis and thus to a reduction in fibrosis of the heart, as well as a decrease in Rho kinase -Activity to weaken the hypertrophy of the heart. The binding of angiotensin (1-9) to the AT 2 receptor in blood vessels promotes vasodilation through increased NO concentration or through crosstalk with the BK 2 receptor. However, the AT 2 receptor leads to increased vasoconstriction under angiotensin- (1-9). The increased NO concentration is to be regarded as a delayed compensation reaction. The main effect, however, is the clear vasoconstriction under angiotensin II. The protective effect is mainly based on the capillary end flow path. The other angiotensin-II degradation products play a relatively minor role in medicine.

mechanism

ACE2 catalyzes the hydrolysis of peptide bonds at the C -terminal end with the help of a zinc ion in the active site. With the octapeptide angiotensin II as a substrate , the heptapeptide angiotensin- (1-7) and the amino acid L- phenylalanine are formed . With the decapeptide angiotensin I as substrate, the nonapeptide angiotensin- (1-9) and the amino acid L- leucine are formed . A general peptide is used as a substrate to simplify the illustration of the reaction mechanism .

During the reaction, the enzyme-substrate complex (in 1 ) is first converted to the tetrahedral intermediate (in 2 ). To do this, the zinc-bound water molecule carries out a nucleophilic attack on the carbonyl group of the peptide ( 1 ), which leads to a transfer of protons from the water molecule to the amino acid residue Glu375. At the same time, a proton is transferred from His505 to the nitrogen atom of the amino acid to be split off ( 2 ). This is followed by the disintegration of the tetrahedral intermediate and the cleavage of the peptide bond ( 3 ), which leads to proton transfer from Glu375 to the free amino group of the split-off amino acid ( 4 ). Then a proton is transferred back from the carboxy group of the oligopeptide to His505 directly ( 5 ) or indirectly by proton exchange with the solvent .

Mechanism of ACE2.svg

Coronavirus receptor

SARS-CoV

The SARS coronavirus (SARS-CoV) is able to bind to the human enzyme ACE2 using the spike (S) protein of the virus envelope . When the ACE2 virus complex is transported to the endosomes , the S protein is cleaved by the endopeptidase cathepsin L , so that the virus enters the cell through pH- dependent and receptor-mediated endocytosis (which occurs independently of clathrin and caveolae ). Another possibility for cell entry is the activation of the S protein by TMPRSS2 and the resulting membrane fusion on the cell surface .

The S-protein of SARS-CoV is composed of two subunits. The S1 subunit contains the receptor binding domain ( english receptor-binding domain , RBD), which can bind to ACE2. When the RBD binds to ACE2, this causes conformational changes in the S2 subunit, which facilitate fusion of the virus envelope with the cell membrane . The amino acid residues 424-494 of RBD form the receptor-binding motif ( English receptor-binding motif , RBM). Within the 14 residues of the RBM that are in direct contact with 18 residues of the ACE2, six of them are tyrosine residues that contribute to the specific recognition of ACE2. In addition, several cysteine ​​residues also contribute to recognition through the formation of disulfide bridges . The amino acid residues Asn479 and Thr487 of the RBM influence the course of SARS and the SARS-CoV tropism . Asn479 is present in most of the human SARS-CoV-S protein sequences . Any changes in positions 479 and 487 of the amino acid sequence of the RBD can affect zoonotic or human-to-human transmissions. For a zoonotic transmission (in the case of SARS transmission of SARS-CoV the larvae Rollers on man) has the RBD of larvae Rollers at position 479 a lysine residue , the to steric hindrance and electrostatic interference with residues of the N -terminal helix of ACE2 as His34 leads. With a Lys479 → Asn479 mutation , the obstructive interactions with the N -terminal helix are avoided and the affinity between RBD and ACE2 is increased, so that it could play a role in zoonotic transmission. In addition, the salt bridges formed in a hydrophobic environment between Lys31 and Glu35 of human ACE2 serve to release binding energy and thus to increase virus-receptor interactions. Thr487 also increases the affinity between RBD and ACE2. The γ- methyl group of Thr487 ensures that the side chain of Lys353 on ACE2 is positioned in such a way that a salt bridge is formed with Asp38 on ACE2 and could thus play a role in human-to-human transmission.

RBD in complex with ACE2.png
ACE2-Active1.png
ACE2-Active2.png
ACE2-Active3.png
Ribbon model of the receptor-binding domain (RBD, cyan ) of the S-protein of SARS-CoV, which is bound to the receptor-binding motif (RBM, red ) on the human receptor ACE2 ( green ). According to PDB  2AJF .
The amino acid residue Leu472 on the RBM enters into hydrophobic interactions with Met82 and Leu79 of the ACE2 and thereby leads to an increase in the affinity between the RBD and the ACE2. A Leu472 → Pro472 mutation at the RBM could weaken the interactions that could have contributed to the end of the SARS pandemic in 2002/2003 .
A previous Lys479 → Asn479 mutation at the RBM and the formation of salt bridges between Glu35 and Lys31 (dashed lines) led to an increase in virus-receptor interactions, which could have an influence on zoonotic transmission.
Thr487, with its methyl group, creates a salt bridge between Lys353 and Asp38 (dashed line) to increase the affinity between RBD and ACE2, which may have played a role in human-to-human transmissions. The subsequent Thr487 → Ser487 mutation on the RBM could lead to a weakening of the interactions that could have contributed to the end of the SARS pandemic of 2002/2003.

SARS-CoV-2

In the event of a SARS-CoV-2 infection, the virion has contact with human cells and is absorbed into the cell interior. In most cells, this process is triggered by the binding of the spike protein in the virus envelope to an ACE2 protein in the cell membrane. The cellular serine protease TMPRSS2 is usually required for penetration. If SARS-CoV-2 penetrates into alveolar epithelial cells ( pneumocytes ), this can lead to respiratory symptoms.

These symptoms are more severe in patients with pre-existing cardiovascular disease, presumably due to an increased ACE2 density on the cell membrane compared to healthy individuals. By increasing the ACE2 level, the equilibrium is shifted in the direction of the counter-regulatory axis. The SARS-CoV-2 infection via ACE2 leads to the inflammation-promoting cytokine release via the angiotensin II-AT 1 R axis; this represents a possible therapeutic target via the IL-6 - STAT3 axis.

Treatment with inhibitors of the renin-angiotensin-aldosterone system ( RAAS inhibitors ) has an influence on the extent of the infection. Different RAAS inhibitors each have different effects on the ACE2 level. In Lewis rats ( laboratory rats developed in the 1950s ), when either ACE inhibitors or angiotensin receptor blockers were administered, the Ace2 mRNA level was increased compared to rats given placebos . In particular in the heart of the rat, the Ace2 mRNA level is increased 4.7-fold when treated with lisinopril and 2.8-fold when treated with losartan . ACE2 activity is increased with lisinopril treatment, but not with losartan treatment, compared to placebo. When treated with captopril , ACE2 expression can be increased significantly in rats with acute lung failure . In rat models of acute lung failure, ACE activity and angiotensin II expression are increased, whereas ACE2 activity and angiotensin (1-7) expression are reduced.

While angiotensin receptor blockers and mineralocorticoid receptor blockers have been shown to increase ACE2 expression and activity in various experimental and clinical models, administration of ACE inhibitors increases the Ace2 mRNA levels of the heart, but did not have any in experimental models Influence on ACE2 activity. In addition, in an animal model of diabetic nephropathy, administration of aliskiren (a direct renin inhibitor ) was associated with a reduction in ACE2 expression. For the treatment of COVID-19 , the YouAn Hospital in Beijing ( Chinese 北京 佑安 医院 ) used intravenous transplantation of ACE2-negative mesenchymal stem cells (MSC), especially for patients in critical condition.

There are clinical concerns about ACE2 regulation with RAAS inhibitors and statins for the treatment of COVID-19.

The German Federal Institute for Drugs and Medical Devices has approved a clinical trial of a recombinant ACE2 on seriously ill COVID-19 patients.

See also

Individual evidence

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