Angiotensin-converting enzyme 2 | M2: Angiotensin-converting (ACE and ACE2) | IUPHAR/BPS Guide to PHARMACOLOGY

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Angiotensin-converting enzyme 2

Target not currently curated in GtoImmuPdb

Target id: 1614

Nomenclature: Angiotensin-converting enzyme 2

Abbreviated Name: ACE2

Family: M2: Angiotensin-converting (ACE and ACE2)

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 788 Xp22 ACE2 angiotensin I converting enzyme 2
Mouse 1 788 X 76.12 cM Ace2 angiotensin I converting enzyme (peptidyl-dipeptidase A) 2
Rat 1 788 Xq21 Ace2 angiotensin I converting enzyme 2
Previous and Unofficial Names
ACE-related carboxypeptidase | renal angiotensin-converting enzyme 2 | angiotensin I converting enzyme (peptidyl-dipeptidase A) 2
Database Links
Specialist databases
MEROPS M02.006 (Hs)
Other databases
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
SynPHARM
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.4.15.1
Binding dissociation constants for SARS-CoVs (Kd) (Human)
SARS-CoV-2 (1.2 nM); SARS-CoV (5 nM); Binding of hACE2 ectodomain to immobilised SB domains of the viral strains in a biolayer interferometry assay.  [13]
Endogenous substrates (Human)
angiotensin I (AGT, P01019) > angiotensin-(1-9) (AGT, P01019)  [1]

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
XNT [PMID: 18391097] Hs Activation 4.7 pEC50 3
pEC50 4.7 (EC50 2.01x10-5 M) [3]
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 28 [PMID: 18324760] Hs Inhibition 9.9 pKi 9
pKi 9.9 (Ki 1.3x10-10 M) [9]
MLN-4760 Hs Inhibition 9.4 pIC50 9
pIC50 9.4 (IC50 4.4x10-10 M) [9]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Abz-Ser-Pro-Tyr(NO2)-OH Hs Binding - - 14
[14]
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 2 GO processes
GO:0001618 virus receptor activity IDA
GO:0046718 viral entry into host cell TAS
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0050727 regulation of inflammatory response IC
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0050727 regulation of inflammatory response IC
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0001817 regulation of cytokine production IC
Tissue Distribution
Nasal goblet and ciliated airway cells
Species:  Human
Technique:  Single-cell RNA-sequencing
References:  12
Spermatogonia, leydig and sertoli cells
Species:  Human
Technique:  Single-cell RNA sequencing
References: 
General Comments
Accumulating data suggest ACE2 as a docking site for the novel coronavirus (officially named SARS-CoV-2) that was identified as the cause of the respiratory disease outbreak in Wuhan in late 2019 [2,4,6-7,10,13]. SARS-CoV-2 was referred to as 2019-nCoV, or Wuhan coronavirus prior to formal naming by the International Committee on Taxonomy of Viruses (ICTV). SARS-CoV-2 is a betacoronavirus, and in common with the original SARS-CoV, the viral spike protein has been shown to engage ACE2 [8,11,13] for viral entry.

ACE2 converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), with Ang1-7 acting as a functional antagonist of Ang1-8. Enhancing ACE2 activity by exogenous administration of ACE2 might be beneficial in human diseases with pathologically elevated Ang1-8, such as may occur when ACE2 is disrupted during the SARS-CoV-2 infection process. Soluble human ACE2, either exogenous recombinant protein or upregulated release of membrane bound endogenous ACE2 via activation of the sheddase ADAM17, could act as a decoy for SARS-CoV-2 viruses, as potential mechanisms to combat infection and/or pathophysiological symptoms. Soluble ACE2 has theoretical potential to both reduce infection capacity and to reduce lung tissue damage during ongoing infection. GSK have already completed a Phase 2 study of their recombinant human ACE2 protein (GSK2586881) to determine its effects in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) [5]. GSK2586881 modulated the renin-angiotensin system (RAS) as expected, but the trial was terminated following a planned futility analysis. A clinical trial (NCT04287686) is planned to gather preliminary biologic, physiologic, and clinical data on the effects of using recombinant human ACE2 protein (we believe this is also using GSK2586881) as a decoy for SARS-CoV-2 in patients with COVID-19.

References

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1. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R et al.. (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res., 87 (5): E1-9. [PMID:10969042]

2. Gralinski LE, Menachery VD. (2020) Return of the Coronavirus: 2019-nCoV. Viruses, 12 (2). DOI: 10.3390/v12020135 [PMID:31991541]

3. Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA, Castellano RK, Lampkins AJ, Gubala V, Ostrov DA et al.. (2008) Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension, 51 (5): 1312-7. [PMID:18391097]

4. Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. (2020) The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv,: 929042. DOI: 10.1101/2020.01.31.929042

5. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M et al.. (2017) A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care, 21 (1): 234. [PMID:28877748]

6. Lei C, Fu W, Qian K, Li T, Zhang S, Ding M, Hu S. (2020) Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig. BioRxiv,: 929976. DOI: 10.1101/2020.02.01.929976

7. Letko M, Munzter V. (2020) Functional assessment of cell entry and receptor usage for lineage B β-coronaviruses, including 2019-nCoV. BiorXiv, (22 January). DOI: 10.1101/2020.01.22.915660

8. Li F, Li W, Farzan M, Harrison SC. (2005) Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science, 309 (5742): 1864-8. [PMID:16166518]

9. Mores A, Matziari M, Beau F, Cuniasse P, Yiotakis A, Dive V. (2008) Development of potent and selective phosphinic peptide inhibitors of angiotensin-converting enzyme 2. J. Med. Chem., 51 (7): 2216-26. [PMID:18324760]

10. Peng Z, Shi Z-L. (2020) Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. BiorXiv, (23 January). DOI: 10.1101/2020.01.22.914952

11. Song W, Gui M, Wang X, Xiang Y. (2018) Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog., 14 (8): e1007236. [PMID:30102747]

12. Sungnak W, Huang N, Becavin C, Berg M, HCA Lung Biological Network. (2020) SARS-CoV-2 Entry Genes Are Most Highly Expressed in Nasal Goblet and Ciliated Cells within Human Airways. arxiv.org, Preprint.

13. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. (2020) Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 181 (2): 281-292.e6. [PMID:32155444]

14. Yan ZH, Ren KJ, Wang Y, Chen S, Brock TA, Rege AA. (2003) Development of intramolecularly quenched fluorescent peptides as substrates of angiotensin-converting enzyme 2. Anal. Biochem., 312 (2): 141-7. [PMID:12531198]

How to cite this page

M2: Angiotensin-converting (ACE and ACE2): Angiotensin-converting enzyme 2. Last modified on 16/04/2020. Accessed on 07/07/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1614.