View source for Angiotensin-converting enzyme 2

{{Short description|Exopeptidase enzyme that acts on angiotensin I and II}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Redirect|ACE2|other uses|Ace 2 (disambiguation)}}
{{Infobox_gene}}

'''Angiotensin-converting enzyme 2''' ('''ACE2''')<ref name="NCBI_ACE2">{{cite web|title=Gene: ACE2, angiotensin I converting enzyme 2 |work=[[National Center for Biotechnology Information]] (NCBI) |publisher=U.S. National Library of Medicine | date=2020-02-28 | url=https://www.ncbi.nlm.nih.gov/gene/59272 }}</ref> is an [[enzyme]] that can be found either attached to the [[cell membrane|membrane]] of cells (mACE2) in the [[intestines]], [[kidney]], [[testis]], [[gallbladder]], and [[heart]] or in a soluble form (sACE2).<ref name="Hikmet et al 2020">{{cite journal | vauthors = Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C | title = The protein expression profile of ACE2 in human tissues | journal = Molecular Systems Biology | volume = 16 | issue = 7 | pages = e9610 | date = July 2020 | pmid = 32715618 | pmc = 7383091 | doi = 10.15252/msb.20209610 | doi-access = free }}</ref><ref name="Tissue distribution of ACE2 protein">{{cite journal | vauthors = Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H | title = Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis | journal = The Journal of Pathology | volume = 203 | issue = 2 | pages = 631–637 | date = June 2004 | pmid = 15141377 | pmc = 7167720 | doi = 10.1002/path.1570 | doi-access = free }}</ref><ref name="pmid10969042">{{cite journal | vauthors = Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S | title = A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 | journal = Circulation Research | volume = 87 | issue = 5 | pages = E1–E9 | date = September 2000 | pmid = 10969042 | doi = 10.1161/01.RES.87.5.e1 | doi-access = free }}</ref> 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. mACE2 is cleaved by the enzyme ADAM17 in a process regulated by [[substrate presentation]].  ADAM17 cleavage releases the extracellular domain creating soluble ACE2 (sACE2).<ref>{{Cite journal |last1=Lambert |first1=Daniel W. |last2=Yarski |first2=Mike |last3=Warner |first3=Fiona J. |last4=Thornhill |first4=Paul |last5=Parkin |first5=Edward T. |last6=Smith |first6=A. Ian |last7=Hooper |first7=Nigel M. |last8=Turner |first8=Anthony J. |date=August 2005 |title=Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2) |journal=Journal of Biological Chemistry |language=en |volume=280 |issue=34 |pages=30113–30119 |doi=10.1074/jbc.M505111200 |doi-access=free |pmc=8062222 |pmid=15983030}}</ref> ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the [[hydrolysis]] of [[angiotensin II]] (a [[vasoconstrictor]] [[peptide]] which raises blood pressure) into [[Angiotensin (1-7)|angiotensin (1–7)]]  (a [[vasodilator]]).<ref name="pmid10969042" /><ref name="pmid17049503">{{cite journal | vauthors = Keidar S, Kaplan M, Gamliel-Lazarovich A | title = ACE2 of the heart: From angiotensin I to angiotensin (1-7) | journal = Cardiovascular Research | volume = 73 | issue = 3 | pages = 463–469 | date = February 2007 | pmid = 17049503 | doi = 10.1016/j.cardiores.2006.09.006 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY | title = Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System | journal = Hypertension | volume = 68 | issue = 2 | pages = 365–377 | date = August 2016 | pmid = 27217402 | doi = 10.1161/HYPERTENSIONAHA.115.06892 | s2cid = 829514 | doi-access = free }}</ref> Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.<ref name="Chamsi-Pasha_2014_2">{{cite journal | vauthors = Chamsi-Pasha MA, Shao Z, Tang WH | title = Angiotensin-converting enzyme 2 as a therapeutic target for heart failure | journal = Current Heart Failure Reports | volume = 11 | issue = 1 | pages = 58–63 | date = March 2014 | pmid = 24293035 | pmc = 3944399 | doi = 10.1007/s11897-013-0178-0 | publisher = Springer Science and Business Media LLC | quote = The discovery of ACE2 and its role in counteracting the effect of Ang-II through Ang(1-7) formation ... An imbalance in ACE2/Ang-(1–7) and ACE/Ang-II axes is critical in the development of cardiovascular diseases. The central role of ACE2, therefore, appears to counter ACE activity by reducing Ang-II bioavailability and increasing Ang(1-7) formation ... The use of RAS-modulating agents and molecules as novel therapeutic agents in hypertension and cardiovascular therapeutic research. }}</ref> This decrease in blood pressure makes the entire process a promising drug target for treating [[cardiovascular disease]]s.<ref name="Chamsi-Pasha_2014">{{cite journal | vauthors = Chamsi-Pasha MA, Shao Z, Tang WH | title = Angiotensin-converting enzyme 2 as a therapeutic target for heart failure | journal = Current Heart Failure Reports | volume = 11 | issue = 1 | pages = 58–63 | date = March 2014 | pmid = 24293035 | pmc = 3944399 | doi = 10.1007/s11897-013-0178-0 | publisher = Springer Science and Business Media LLC | quote = Studies with recombinant human ACE2 (rhACE2) have shown beneficial cardiac effects [18, 36]. rhACE2 has anti-fibrotic properties and can attenuate effect on systolic and diastolic dysfunction, presumably via Ang-II inhibition. }}</ref><ref name="Mascolo_2020">{{cite journal | vauthors = Mascolo A, Urbanek K, De Angelis A, Sessa M, Scavone C, Berrino L, Rosano GM, Capuano A, Rossi F | title = Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation? | journal = Heart Failure Reviews | volume = 25 | issue = 2 | pages = 367–380 | date = March 2020 | pmid = 31375968 | doi = 10.1007/s10741-019-09837-7 | publisher = Springer Science and Business Media LLC | quote = the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research. | s2cid = 199388175 | url = http://openaccess.sgul.ac.uk/111404/1/Manuscript%20Ang-AF.docx }}</ref>

mACE2 also serves as the entry point into cells for some [[coronaviruses]], including [[HCoV-NL63]], [[SARS-CoV]], and [[SARS-CoV-2]].<ref name="NCBI_ACE2"/> While mACE2's function is not that of a [[Receptor (biochemistry)|biological receptor]], because of its receptor-like interaction with viruses it is also referred to as the '''ACE2 receptor'''.<ref>{{Cite web |last=Sriram |first=Krishna |last2=Insel |first2=Paul |last3=Loomba |first3=Rohit |title=What is the ACE2 receptor? |url=https://www.asbmb.org/asbmb-today/science/051620/what-is-the-ace2-receptor |access-date=2025-05-25 |website=www.asbmb.org |language=en}}</ref> The human version of the enzyme can be referred to as hACE2.<ref name="Ennaji_2019">{{cite book | vauthors = Kasmi Y, Khataby K, Souiri A |chapter=Coronaviridae: 100,000 Years of Emergence and Reemergence | chapter-url= https://books.google.com/books?id=4l6wDwAAQBAJ&pg=PA135 | veditors = Ennaji MM | volume = 1 | title =Emerging and Reemerging Viral Pathogens: Fundamental and Basic Virology Aspects of Human, Animal and Plant Pathogens |date=2019 |publisher=Elsevier |isbn=978-0-12-819400-3 |page=135 }}</ref>

== Structure ==
{{enzyme
| Name = Angiotensin-converting enzyme 2
| EC_number = 3.4.17.23
| CAS_number =
| IUBMB_EC_number =
| GO_code =
| width =
| caption =
|align=left
}}
Membrane bound angiotensin-converting enzyme 2 (mACE2) is a zinc-containing [[metalloenzyme]] located on the surface of intestinal [[enterocytes]], renal tubular cells and other cells.<ref name="Hikmet et al 2020" /><ref name = "Turner_2015">{{cite book | vauthors = Turner AJ | s2cid = 88645177 | chapter = Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions | veditors = Unger T, Ulrike M, Steckelings UM, dos Santos RA | title = The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications | date = 2015 | pages = 185–189 | doi = 10.1016/B978-0-12-801364-9.00025-0 | isbn = 978-0-12-801364-9 | publisher = Academic Press }}</ref> mACE2 protein contains an [[N-terminal]] peptidase M2 domain and a [[C-terminal]] collectrin renal [[amino acid transporter]] domain.<ref name = "Turner_2015" />

mACE2 is a single-pass [[type I membrane protein]], with its enzymatically active [[protein domain|domain]] exposed on the surface of cells in the intestines and other tissues.<ref name="Hikmet et al 2020" /><ref name="Tissue distribution of ACE2 protein"/> The extracellular domain of mACE2 can be [[Proteolysis|cleaved]] from the [[transmembrane domain]] by another enzyme known as [[ADAM17]] a member of the [[sheddase]] enzyme family, during the protective phase of [[Renin–angiotensin system|RAAS]], the Renin–Angiotensin–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.<ref>{{cite journal | vauthors = Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ | title = Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) | journal = The Journal of Biological Chemistry | volume = 280 | issue = 34 | pages = 30113–30119 | date = August 2005 | pmid = 15983030 | pmc = 8062222 | doi = 10.1074/jbc.M505111200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY | title = Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS | journal = Journal of Molecular and Cellular Cardiology | volume = 66 | pages = 167–176 | date = January 2014 | pmid = 24332999 | doi = 10.1016/j.yjmcc.2013.11.017 | doi-access = free }}</ref>{{clear|left}}

== Location within the human body == 
mACE2 is attached to the cell membrane of mainly [[enterocyte]]s of the [[small intestine]] and [[duodenum]], [[proximal tubular]] cells of the [[kidney]]s, glandular cells of the [[gallbladder]], as well as [[Sertoli cells]] and [[Leydig cells]] of the [[testis]].<ref name="Hikmet et al 2020" /> The expression profile of mACE2 in the human body was recently thoroughly evaluated by the [[Human Protein Atlas]] 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.<ref name="Hikmet et al 2020" /><ref name="ACE2 - The Human Protein Atlas">{{cite web |last1=The Human Protein Atlas |title=ACE2 protein expression summary |url=https://www.proteinatlas.org/ENSG00000130234-ACE2 |website=www.proteinatlas.org |access-date=12 May 2021}}</ref> In addition to the above-mentioned issues, mACE2 expression was also seen in [[endothelial cells]] and [[pericytes]] of blood vessels within certain tissues, [[cardiomyocytes]] in heart tissue, and a smaller subset of cells within the [[thyroid gland]], [[epididymis]], [[seminal vesicle]], [[pancreas]], [[liver]] and [[placenta]]. Despite the fact that the [[respiratory system]] is the primary route of [[SARS-CoV-2]] 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]], especially in the [[cilia|ciliated cells]].<ref name="pmid34611326">{{cite journal | vauthors = Jackson CB, Farzan M, Chen B, Choe H | title = Mechanisms of SARS-CoV-2 entry into cells | journal = Nature Reviews. Molecular Cell Biology | volume = 23 | issue = 1 | pages = 3–20 | date = January 2022 | pmid = 34611326 | pmc = 8491763 | doi = 10.1038/s41580-021-00418-x }}</ref>

== 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]] hormone into the vasoconstricting  [[angiotensin II]] 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)]], thereby lowering blood pressure.<ref name="pmid34745001">{{cite journal | vauthors = Hu Y, Liu L, Lu X | title = Regulation of Angiotensin-Converting Enzyme 2: A Potential Target to Prevent COVID-19? | journal = Frontiers in Endocrinology | volume = 12 | pages = 725967 | date = 2021 | pmid = 34745001 | pmc = 8569797 | doi = 10.3389/fendo.2021.725967 | doi-access = free }}</ref><ref name="pmid34934510">{{cite journal | vauthors = Singh B, Singh D, Verma V, Yadav R, Kumar R | title = Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19: A review | journal = Journal of Pharmaceutical Analysis | date = December 2021 | volume = 12 | issue = 2 | pages = 215–220 | pmid = 34934510 | pmc = 8677424 | doi = 10.1016/j.jpha.2021.12.003 }}</ref>

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)]] (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure.<ref>{{cite journal | vauthors = Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T | title = Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 14 | pages = 8258–8263 | date = July 2003 | pmid = 12829792 | pmc = 166216 | doi = 10.1073/pnas.1432869100 | doi-access = free | bibcode = 2003PNAS..100.8258S }}</ref><ref name = "Turner_2015" />  sACE2 can also cleave numerous peptides, including {{nowrap|[des-Arg9]-[[bradykinin]]}}, [[apelin]], [[neurotensin]], [[dynorphin A]], and [[ghrelin]].<ref name = "Turner_2015" />

mACE2 also regulates the membrane trafficking of the neutral amino acid transporter [[SLC6A19]] and has been implicated in [[Hartnup's disease]].<ref name="Kowalczuk_2008">{{cite journal | vauthors = Kowalczuk S, Bröer A, Tietze N, Vanslambrouck JM, Rasko JE, Bröer S | title = A protein complex in the brush-border membrane explains a Hartnup disorder allele | journal = FASEB Journal | volume = 22 | issue = 8 | pages = 2880–2887 | date = August 2008 | pmid = 18424768 | doi = 10.1096/fj.08-107300 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fairweather SJ, Bröer A, Subramanian N, Tumer E, Cheng Q, Schmoll D, O'Mara ML, Bröer S | title = Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin | journal = The Journal of Biological Chemistry | volume = 290 | issue = 40 | pages = 24308–24325 | date = October 2015 | pmid = 26240152 | pmc = 4591816 | doi = 10.1074/jbc.M115.648519 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q | title = Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 | journal = Science | volume = 367 | issue = 6485 | pages = 1444–1448 | date = March 2020 | pmid = 32132184 | pmc = 7164635 | doi = 10.1126/science.abb2762 | bibcode = 2020Sci...367.1444Y | doi-access = free }}</ref>

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.<ref name="pmid18956256">{{cite journal | vauthors = Niu MJ, Yang JK, Lin SS, Ji XJ, Guo LM | title = Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice | journal = Endocrine | volume = 34 | issue = 1–3 | pages = 56–61 | date = 2008 | pmid = 18956256 | doi = 10.1007/s12020-008-9110-x | s2cid = 46331895 }}</ref><ref name="pmid22227126">{{cite journal | vauthors = Putnam K, Shoemaker R, Yiannikouris F, Cassis LA | title = The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 302 | issue = 6 | pages = H1219–H1230 | date = March 2012 | pmid = 22227126 | pmc = 3311482 | doi = 10.1152/ajpheart.00796.2011 }}</ref>

== Coronavirus entry point ==
As a transmembrane protein, mACE2 serves as the main entry point into cells for some [[coronavirus]]es, including [[HCoV-NL63]],<ref name="NCBI_ACE2"/> [[SARS-CoV]] (the [[virus]] that causes [[SARS]]),<ref name="Fehr_2015">{{cite book | vauthors = Fehr AR, Perlman S | title = Coronaviruses | chapter = Coronaviruses: an overview of their replication and pathogenesis | series = Methods in Molecular Biology | volume = 1282 | pages = 1–23 | year = 2015 | pmid = 25720466 | pmc = 4369385 | doi = 10.1007/978-1-4939-2438-7_1 | publisher = Springer New York | isbn = 978-1-4939-2437-0 | quote = Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors). }}</ref><ref>{{cite journal | vauthors = Li F | title = Receptor recognition and cross-species infections of SARS coronavirus | journal = Antiviral Research | volume = 100 | issue = 1 | pages = 246–254 | date = October 2013 | pmid = 23994189 | pmc = 3840050 | doi = 10.1016/j.antiviral.2013.08.014 }}</ref><ref name = "Imai_2005">{{cite journal | vauthors = Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM | title = A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury | journal = Nature Medicine | volume = 11 | issue = 8 | pages = 875–879 | date = August 2005 | pmid = 16007097 | pmc = 7095783 | doi = 10.1038/nm1267 }}</ref> and [[SARS-CoV-2]]<ref>{{cite web |title=What are the official names of the disease and the virus that causes it? |url=https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |website=Q&A on coronaviruses |publisher=World Health Organization |access-date=22 February 2020 |archive-url=https://web.archive.org/web/20200305015146/https://www.who.int/news-room/q-a-detail/q-a-coronaviruses |archive-date=5 March 2020 |url-status=live }}</ref> (the virus that causes [[COVID-19]]).<ref>{{cite journal | vauthors = Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL | title = A pneumonia outbreak associated with a new coronavirus of probable bat origin | journal = Nature | volume = 579 | issue = 7798 | pages = 270–273 | date = March 2020 | pmid = 32015507 | pmc = 7095418 | doi = 10.1038/s41586-020-2012-7 | bibcode = 2020Natur.579..270Z }}</ref><ref>{{cite journal | vauthors = Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, Zhong W, Hao P | title = Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission | journal = Science China Life Sciences | volume = 63 | issue = 3 | pages = 457–460 | date = March 2020 | pmid = 32009228 | pmc = 7089049 | doi = 10.1007/s11427-020-1637-5 }}</ref><ref>{{cite web | vauthors = Lewis R  |title=COVID-19 Vaccine Will Close in on the Spikes |url= https://blogs.plos.org/dnascience/2020/02/20/covid-19-vaccine-will-close-in-on-the-spikes/ |website=DNA Science Blog |publisher= Public Library of Science |date=2020-02-20 |access-date=2020-02-22 |archive-url= https://web.archive.org/web/20200222102112/https://blogs.plos.org/dnascience/2020/02/20/covid-19-vaccine-will-close-in-on-the-spikes/ |archive-date=2020-02-22 |url-status=live }}</ref><ref name="Zipeto_2020">{{cite journal | vauthors = Zipeto D, Palmeira JD, Argañaraz GA, Argañaraz ER | title = ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19 | journal = Frontiers in Immunology | volume = 11 | issue =  | pages = 576745 | date = 2020 | pmid = 33117379 | pmc = 7575774 | doi = 10.3389/fimmu.2020.576745 | doi-access = free }}</ref><ref name=":0">{{Cite journal |last=Yousefbeigi |first=Sarina |last2=Marsusi |first2=Farah |date=2023-11-20 |title=Structural insights into ACE2 interactions and immune activation of SARS-CoV-2 and its variants: an in-silico study |url=https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2283158 |journal=Journal of Biomolecular Structure and Dynamics |language=en |pages=1–14 |doi=10.1080/07391102.2023.2283158 |issn=0739-1102|url-access=subscription }}</ref>  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]] and [[protein translocation|translocation]] of both the virus and the enzyme into [[endosome]]s located within cells.<ref name="Wang_2008">{{cite journal | vauthors = Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, Jiang C | title = SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway | journal = Cell Research | volume = 18 | issue = 2 | pages = 290–301 | date = February 2008 | pmid = 18227861 | pmc = 7091891 | doi = 10.1038/cr.2008.15 }}</ref><ref name="Millet_2018">{{cite journal | vauthors = Millet JK, Whittaker GR | title = Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells | journal = Virology | volume = 517 | pages = 3–8 | date = April 2018 | pmid = 29275820 | pmc = 7112017 | doi = 10.1016/j.virol.2017.12.015 }}</ref> In culture blocking endocytosis traps the virus on the surface.<ref>{{cite journal | vauthors = Hansen SB, Yuan Z | title = Getting in on the action: New tools to see SARS-CoV-2 infect a cell | journal = Cell Chemical Biology | volume = 30 | issue = 3 | pages = 233–234 | date = March 2023 | pmid = 36931249 | doi = 10.1016/j.chembiol.2023.02.010 | s2cid = 257580098 | pmc = 10018748 }}</ref> The SARS-CoV-2 spike protein itself is known to damage the [[endothelium]] via [[Downregulation and upregulation|downregulation]] of ACE2.<ref>{{cite journal | vauthors = Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H, Zhang Y, Yin Q, Cho Y, Andrade L, Shadel GS, Hepokoski M, Lei T, Wang H, Zhang J, Yuan JX, Malhotra A, Manor U, Wang S, Yuan ZY, Shyy JY | title = SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2 | journal = Circulation Research | volume = 128 | issue = 9 | pages = 1323–1326 | date = April 2021 | pmid = 33784827 | pmc = 8091897 | doi = 10.1161/CIRCRESAHA.121.318902 }}</ref>

The receptor-binding domain (RBD) of spike protein, located on the virus’s surface, specifically attaches to human cell receptors.<ref name=":0" /> ACE2 is essential as it’s a cell surface receptor that lets the virus get into and infect cells. The spike protein’s RBD of SARS-CoV-2 links to ACE2, enabling viral entry and reproduction within cells.<ref name=":0" /> In addition the attachment of SP-A and SP-D residues to ACE2 could potentially diminish the strength of the interaction between the spike protein and ACE2.<ref name=":0" />

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.<ref>{{cite journal | vauthors = Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J | title = SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS | journal = European Journal of Clinical Investigation | volume = 39 | issue = 7 | pages = 618–625 | date = July 2009 | pmid = 19453650 | pmc = 7163766 | doi = 10.1111/j.1365-2362.2009.02153.x }}</ref> It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals.<ref>{{cite journal | vauthors = Rathore SS, Rojas GA, Sondhi M, Pothuru S, Pydi R, Kancherla N, Singh R, Ahmed NK, Shah J, Tousif S, Baloch UT, Wen Q | title = Myocarditis associated with Covid-19 disease: A systematic review of published case reports and case series | journal = International Journal of Clinical Practice | volume = 75 | issue = 11 | pages = e14470 | date = November 2021 | pmid = 34235815 | doi = 10.1111/ijcp.14470 | s2cid = 235768792 | doi-access = free }}</ref> This entry process also requires priming of the S protein by the host serine protease [[TMPRSS2]], the inhibition of which is under current investigation as a potential therapeutic.<ref>{{cite journal | vauthors = Akhmerov A, Marbán E | title = COVID-19 and the Heart | journal = Circulation Research | volume = 126 | issue = 10 | pages = 1443–1455 | date = May 2020 | pmid = 32252591 | pmc = 7188058 | doi = 10.1161/CIRCRESAHA.120.317055 | doi-access = free }}</ref><ref name="pmid34611326" /> It has also been shown that disruption of S-protein [[glycosylation]] significantly impairs viral entry, indicating the importance of [[glycan-protein interactions]] in the process.<ref>{{cite web | vauthors = Novokmet M, Baković MP, Lauc G | date = 1 April 2020 |title= Understanding Glycans in COVID-19 Drug Design |url= https://www.genengnews.com/insights/understanding-glycans-in-covid-19-drug-design/ | work = Genetic Engineering and Biotechnology News |language=en-US |access-date=2020-05-18}}</ref>

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]], 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.<ref name="Imai_2008">{{cite journal | vauthors = Imai Y, Kuba K, Penninger JM | title = The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice | journal = Experimental Physiology | volume = 93 | issue = 5 | pages = 543–548 | date = May 2008 | pmid = 18448662 | pmc = 7197898 | doi = 10.1113/expphysiol.2007.040048 }}</ref><ref name="pmid27082314">{{cite journal | vauthors = Jia H | title = Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease | journal = Shock | volume = 46 | issue = 3 | pages = 239–248 | date = September 2016 | pmid = 27082314 | doi = 10.1097/SHK.0000000000000633 | quote = Once SARS-CoV binds to its receptor, the abundance on the cell surface, mRNA expression and the enzymatic activity of ACE2 are significantly reduced. ... These effects are, in part, due to enhanced shedding/internalizing processes. ... The spike protein binds to ACE2 and subsequently down regulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia | s2cid = 3639219 }}</ref>

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]] [[Angiotensin (1-7)|angiotensin 1–7]].<ref name="Imai_2008" /> 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]]s, hence making those coronavirus spikes unavailable for binding to mACE-2 sites.<ref name="Zipeto_2020" /> But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2 is present.<ref name="pmid33132005">{{cite journal | vauthors = Harrison AG, Lin T, Wang P | title = Mechanisms of SARS-CoV-2 Transmission and Pathogenesis | journal = Trends in Immunology | volume = 41 | issue = 12 | pages = 1100–1115 | date = December 2020 | pmid = 33132005 | pmc = 7556779 | doi = 10.1016/j.it.2020.10.004 }}</ref>

Both [[ACE inhibitor]]s and [[angiotensin II receptor blocker]]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.<ref>{{cite journal | vauthors = Nicholls J, Peiris M | title = Good ACE, bad ACE do battle in lung injury, SARS | journal = Nature Medicine | volume = 11 | issue = 8 | pages = 821–822 | date = August 2005 | pmid = 16079870 | pmc = 7095949 | doi = 10.1038/nm0805-821 }}</ref><ref name="pmid32186711">{{cite journal | vauthors = Diaz JH | title = Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 | journal = Journal of Travel Medicine | volume = 27 | issue = 3 | date = May 2020 | pmid = 32186711 | pmc = 7184445 | doi = 10.1093/jtm/taaa041 | doi-access = free }}</ref>

However, a [[systematic review]] and [[meta-analysis]] 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."<ref name="Caldeira_2012">{{cite journal | vauthors = Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J | title = Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis | journal = BMJ | volume = 345 | issue = jul11 1 | pages = e4260 | date = July 2012 | pmid = 22786934 | pmc = 3394697 | doi = 10.1136/bmj.e4260 | quote = Our results suggest an important role of ACE inhibitors, but not ARBs, in reducing the risk of pneumonia. These data may discourage the withdrawal of ACE inhibitors in some patients with tolerable adverse events (namely, cough) who are at particularly high risk of pneumonia. ACE inhibitors also lowered the risk of pneumonia related mortality, mainly in patients with established disease, but the robustness of the evidence was weaker. }}</ref>  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.<ref name="Zhang 2020">{{cite journal | vauthors = Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Loomba R, Liu PP, Li H | title = Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 | journal = Circulation Research | volume = 126 | issue = 12 | pages = 1671–1681 | date = June 2020 | pmid = 32302265 | pmc = 7265882 | doi = 10.1161/CIRCRESAHA.120.317134 | doi-access = free }}</ref>

Despite lack of conclusive evidence, some have advocated for or against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.<ref name="Patel_2020">{{cite journal | vauthors = Patel AB, Verma A | title = COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? | journal = JAMA | volume = 323 | issue = 18 | pages = 1769–1770 | date = May 2020 | pmid = 32208485 | doi = 10.1001/jama.2020.4812 | doi-access = free }}</ref> However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.<ref name="ESC">{{cite web | title = Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers | url = https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang | work = European Society of Cardiology (ESC) | date = 13 March 2020 }}</ref><ref>{{cite web | title = EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic | url = https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic | work = European Medicines Agency (EMA) | date = 27 March 2020 }}</ref><ref>{{cite web | title = HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 | url = https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19 | work = American College of Cardiology (ACC) | date = 27 March 2020 }}</ref>

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.<ref>{{cite journal | vauthors = Kragstrup TW, Singh HS, Grundberg I, Nielsen AL, Rivellese F, Mehta A, Goldberg MB, Filbin MR, Qvist P, Bibby BM | title = Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients | journal = PLOS ONE | volume = 16 | issue = 6 | pages = e0252799 | year = 2021 | pmid = 34086837 | pmc = 8177449 | doi = 10.1371/journal.pone.0252799 | doi-access = free | bibcode = 2021PLoSO..1652799K }}</ref>

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]] to COVID-19.<ref>{{cite journal | vauthors = Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W | title = Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations | journal = Cell Discovery | volume = 6 | issue = 1 | pages = 11 | date = 2020-02-24 | pmid = 32133153 | pmc = 7040011 | doi = 10.1038/s41421-020-0147-1 }}</ref><ref name="Li_2022">{{cite journal | vauthors = Li J, Wang Y, Liu Y, Zhang Z, Zhai Y, Dai Y, Wu Z, Nie X, Du L | title = Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review | journal = European Journal of Medical Research | volume = 27 | issue = 1 | pages = 26 | date = February 2022 | pmid = 35193695 | pmc = 8861605 | doi = 10.1186/s40001-022-00647-6 | doi-access = free }}</ref> Several studies have reported that ACE2 [[Missense mutation|missense variants]] can alter its [[binding affinity]] for the spike protein,<ref>{{cite journal | vauthors = Suryamohan K, Diwanji D, Stawiski EW, Gupta R, Miersch S, Liu J, Chen C, Jiang YP, Fellouse FA, Sathirapongsasuti JF, Albers PK, Deepak T, Saberianfar R, Ratan A, Washburn G, Mis M, Santhosh D, Somasekar S, Hiranjith GH, Vargas D, Mohan S, Phalke S, Kuriakose B, Antony A, Ustav M, Schuster SC, Sidhu S, Junutula JR, Jura N, Seshagiri S | title = Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2 | journal = Communications Biology | volume = 4 | issue = 1 | pages = 475 | date = April 2021 | pmid = 33846513 | pmc = 8041869 | doi = 10.1038/s42003-021-02030-3 }}</ref><ref>{{cite journal | vauthors = Santos TM, Lisboa AB, Rodrigues W, Gomes H, Abrahão J, Del-Bem LE | title = Human variation in the protein receptor ACE2 affects its binding affinity to SARS-CoV-2 in a variant-dependent manner | journal = Journal of Biomolecular Structure & Dynamics | pages = 2947–2955 | date = February 2022 | volume = 41 | issue = 7 | pmid = 35196964 | doi = 10.1080/07391102.2022.2042387 | s2cid = 247083671 }}</ref><ref name="MacGowan_2022">{{cite journal | vauthors = MacGowan SA, Barton MI, Kutuzov M, Dushek O, van der Merwe PA, Barton GJ | title = Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants | journal = PLOS Computational Biology | volume = 18 | issue = 3 | pages = e1009922 | date = March 2022 | pmid = 35235558 | pmc = 8920257 | doi = 10.1371/journal.pcbi.1009922 | bibcode = 2022PLSCB..18E9922M | doi-access = free }}</ref> and consequently its susceptibility to SARS-CoV-2 pseudovirus entry,<ref name="Shukla_2021">{{cite journal | vauthors = Shukla N, Roelle SM, Suzart VG, Bruchez AM, Matreyek KA | title = Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection | journal = PLOS Pathogens | volume = 17 | issue = 7 | pages = e1009715 | date = July 2021 | pmid = 34270613 | pmc = 8284657 | doi = 10.1371/journal.ppat.1009715 | doi-access = free }}</ref> and there is strong evidence of individuals who carry rare variants in ACE2 that could confer total resistance to SARS-CoV-2 infection.<ref name="MacGowan_2022" /> 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<ref name="Shukla_2021" /> and many suspected COVID-19 associated ACE2 variants affect expression.<ref name="Li_2022" /> In fact, SARS-CoV-2's viral tropism is dependent on ACE2 tissue distribution and expression.<ref>{{cite journal | vauthors = Oudit GY, Wang K, Viveiros A, Kellner MJ, Penninger JM | title = Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic | journal = Cell | volume = 186 | issue = 5 | pages = 906–922 | date = March 2023 | pmid = 36787743 | doi = 10.1016/j.cell.2023.01.039 | s2cid = 256460314 | pmc = 9892333 }}</ref> For example, genetic variants placed in the X chromosome (rs190509934:C) have been related to lower expression levels of ACE2 enzyme. This would lead to an increased number of entries and infections performed by the SARS-CoV-2 virus. Moreover, those variants have shown a 37% reduction in expression of the protein and a remarkable protection from severe outcomes (respiratory failure and death).<ref name="Niemi_2022">{{cite journal | vauthors = Niemi ME, Daly MJ, Ganna A | title = The human genetic epidemiology of COVID-19 | journal = Nature Reviews. Genetics | volume = 23 | issue = 9 | pages = 533–546 | date = September 2022 | pmid = 35501396 | pmc = 9060414 | doi = 10.1038/s41576-022-00478-5 }}</ref>

== Recombinant human ACE2 ==

Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for [[acute lung injury]], and appeared to improve pulmonary [[hemodynamics|blood flow]] and [[Oxygen saturation (medicine)|oxygen saturation]] in [[Piglet (animal)|piglet]]s with a [[lipopolysaccharide]]-induced [[acute respiratory distress syndrome]].<ref name="Colafella_2019">{{cite book | vauthors = Colafella KM, Uijl E, Danser J | chapter=Interference With the Renin–Angiotensin System (RAS): Classical Inhibitors and Novel Approaches | title=Encyclopedia of Endocrine Diseases  | publisher=Elsevier | year=2019 | isbn=978-0-12-812200-6 | doi=10.1016/b978-0-12-801238-3.65341-2 | pages=523–530| s2cid=86384280 }}</ref> 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.<ref name="Colafella_2019"/>  Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic [[renin–angiotensin system inhibitor]]s (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.<ref name="Colafella_2019"/>

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]]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 &ndash; possibly as a decoy.<ref>{{cite journal | vauthors = Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, Romero JP, Wirnsberger G, Zhang H, Slutsky AS, Conder R, Montserrat N, Mirazimi A, Penninger JM | title = Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2 | journal = Cell | volume = 181 | issue = 4 | pages = 905–913.e7 | date = May 2020 | pmid = 32333836 | pmc = 7181998 | doi = 10.1016/j.cell.2020.04.004 | doi-access = free }}</ref> ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise the virus ''in vitro''.<ref name="Chan_2020">{{cite journal | vauthors = Chan KK, Dorosky D, Sharma P, Abbasi SA, Dye JM, Kranz DM, Herbert AS, Procko E | title = Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2 | journal = Science | volume = 369 | issue = 6508 | pages = 1261–1265 | date = September 2020 | pmid = 32753553 | pmc = 7574912 | doi = 10.1126/science.abc0870 | bibcode = 2020Sci...369.1261C }}</ref> An ACE2 triple mutant that displayed nanomolar binding to Spike (sACE2.v2.4),<ref name="Chan_2020" /> 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.<ref>{{cite journal | vauthors = Zhang L, Dutta S, Xiong S, Chan M, Chan KK, Fan TM, Bailey KL, Lindeblad M, Cooper LM, Rong L, Gugliuzza AF, Shukla D, Procko E, Rehman J, Malik AB | title = Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants | journal = Nature Chemical Biology | volume = 18 | issue = 3 | pages = 342–351 | date = March 2022 | pmid = 35046611 | pmc = 8885411 | doi = 10.1038/s41589-021-00965-6 }}</ref>

Infused rhACE2 has been evaluated in clinical trials for the treatment of [[acute respiratory distress syndrome]] (ARDS).<ref>{{cite journal | vauthors = Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, Hall R, Poirier G, Ronco JJ, Tidswell M, Hardes K, Powley WM, Wright TJ, Siederer SK, Fairman DA, Lipson DA, Bayliffe AI, Lazaar AL | title = A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome | journal = Critical Care | volume = 21 | issue = 1 | pages = 234 | date = September 2017 | pmid = 28877748 | pmc = 5588692 | doi = 10.1186/s13054-017-1823-x | doi-access = free }}</ref> rhACE2 is in phase II trial for severe COVID-19.<ref>{{cite news|title=Apeiron Biologics moves forward with APN01 for treatment of COVID-19|work=www.thepharmaletter.com|url=https://www.thepharmaletter.com/article/apeiron-biologics-moves-forward-with-apn01-for-treatment-of-covid-19|access-date=3 April 2020}}</ref>

== See also ==
* [[Renin–angiotensin system]]
* [[SARS-CoV-2#Virology|SARS-CoV-2 § Virology]]
* [[LRRC15]]
{{clear}}

== References ==
{{Reflist}}

== External links ==
* {{UCSC gene info|ACE2}}
* [https://membranome.org/proteins/153 Angiotensin-converting enzyme 2] in [[Membranome database]]
* [https://opm.phar.umich.edu/proteins/5000 3D structure] of [[protein complex|complex]] of a [[neurotransmitter sodium symporter]] [[Sodium-dependent neutral amino acid transporter B(0)AT1|B(0)AT1]], ACE2, and [[SARS-CoV-2]]  receptor-binding domain in [[OPM database]]
* {{PDBe-KB2|Q9BYF1|Angiotensin-converting enzyme 2}}

{{Proteases}}
{{Enzymes}}
{{Portal bar|Medicine|Biology}}

[[Category:EC 3.4.17]]
[[Category:Single-pass transmembrane proteins]]