Angiotensin Converting Enzymes
Identifieur interne : 000971 ( Pmc/Corpus ); précédent : 000970; suivant : 000972Angiotensin Converting Enzymes
Auteurs : Marty K. S. WongSource :
- Handbook of Hormones ; 2015.
Abstract
Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. Researches on domain specific ACE inhibitors are continuing to produce effective hypertension controlling drugs with fewer side effects. ACE2 was discovered in 2000; it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus causing the infamous severe acute respiratory syndrome (SARS) in 2003.
Url:
DOI: 10.1016/B978-0-12-801028-0.00254-3
PubMed: NONE
PubMed Central: 7150253
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Angiotensin Converting Enzymes</title><author><name sortKey="Wong, Marty K S" sort="Wong, Marty K S" uniqKey="Wong M" first="Marty K. S." last="Wong">Marty K. S. Wong</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7150253</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150253</idno><idno type="RBID">PMC:7150253</idno><idno type="doi">10.1016/B978-0-12-801028-0.00254-3</idno><idno type="pmid">NONE</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000971</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000971</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Angiotensin Converting Enzymes</title><author><name sortKey="Wong, Marty K S" sort="Wong, Marty K S" uniqKey="Wong M" first="Marty K. S." last="Wong">Marty K. S. Wong</name></author></analytic><series><title level="j">Handbook of Hormones</title><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. Researches on domain specific ACE inhibitors are continuing to produce effective hypertension controlling drugs with fewer side effects. ACE2 was discovered in 2000; it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus causing the infamous severe acute respiratory syndrome (SARS) in 2003.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bernstein, K E" uniqKey="Bernstein K">K.E. Bernstein</name></author><author><name sortKey="Ong, F S" uniqKey="Ong F">F.S. Ong</name></author><author><name sortKey="Blackwell, W L" uniqKey="Blackwell W">W.L. Blackwell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tipnis, S R" uniqKey="Tipnis S">S.R. Tipnis</name></author><author><name sortKey="Hooper, N M" uniqKey="Hooper N">N.M. Hooper</name></author><author><name sortKey="Hyde, R" uniqKey="Hyde R">R. Hyde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donoghue, M" uniqKey="Donoghue M">M. Donoghue</name></author><author><name sortKey="Hsieh, F" uniqKey="Hsieh F">F. Hsieh</name></author><author><name sortKey="Baronas, E" uniqKey="Baronas E">E. Baronas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Soubrier, F" uniqKey="Soubrier F">F. Soubrier</name></author><author><name sortKey="Wei, L" uniqKey="Wei L">L. Wei</name></author><author><name sortKey="Hubert, C" uniqKey="Hubert C">C. Hubert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chou, C F" uniqKey="Chou C">C.F. Chou</name></author><author><name sortKey="Loh, C B" uniqKey="Loh C">C.B. Loh</name></author><author><name sortKey="Foo, Y K" uniqKey="Foo Y">Y.K. Foo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, R" uniqKey="Zhang R">R. Zhang</name></author><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y. Wu</name></author><author><name sortKey="Zhao, M" uniqKey="Zhao M">M. Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Erdos, E G" uniqKey="Erdos E">E.G. Erdös</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Georgiadis, D" uniqKey="Georgiadis D">D. Georgiadis</name></author><author><name sortKey="Cuniasse, P" uniqKey="Cuniasse P">P. Cuniasse</name></author><author><name sortKey="Cotton, J" uniqKey="Cotton J">J. Cotton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clarke, N E" uniqKey="Clarke N">N.E. Clarke</name></author><author><name sortKey="Turner, A J" uniqKey="Turner A">A.J. Turner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cole, J" uniqKey="Cole J">J. Cole</name></author><author><name sortKey="Ertoy, D" uniqKey="Ertoy D">D. Ertoy</name></author><author><name sortKey="Bernstein, K E" uniqKey="Bernstein K">K.E. Bernstein</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="chapter-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Handbook of Hormones</journal-id><journal-title-group><journal-title>Handbook of Hormones</journal-title></journal-title-group></journal-meta><article-meta><article-id pub-id-type="pmc">7150253</article-id><article-id pub-id-type="publisher-id">B978-0-12-801028-0.00254-3</article-id><article-id pub-id-type="doi">10.1016/B978-0-12-801028-0.00254-3</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Angiotensin Converting Enzymes</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0010"><name><surname>Wong</surname><given-names>Marty K.S.</given-names></name></contrib></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Takei</surname><given-names>Yoshio</given-names></name></contrib></contrib-group><aff>Atmosphere and Ocean Research Institute, The University of Tokyo, Chiba, Japan</aff><contrib-group><contrib contrib-type="editor"><name><surname>Ando</surname><given-names>Hironori</given-names></name></contrib></contrib-group><aff>Sado Marine Biological Station, Faculty of Science, Niigata University, Niigata, Japan</aff><contrib-group><contrib contrib-type="editor"><name><surname>Tsutsui</surname><given-names>Kazuyoshi</given-names></name></contrib></contrib-group><aff>Department of Biology and Center for Medical Life Science, Waseda University, Tokyo, Japan</aff><pub-date pub-type="pmc-release"><day>4</day><month>9</month><year>2015</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><year>2016</year></pub-date><pub-date pub-type="epub"><day>4</day><month>9</month><year>2015</year></pub-date><fpage>263</fpage><lpage>e29D-4</lpage><permissions><copyright-statement>Copyright © 2016 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Elsevier Inc.</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="ab0010"><p>Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. Researches on domain specific ACE inhibitors are continuing to produce effective hypertension controlling drugs with fewer side effects. ACE2 was discovered in 2000; it converts Ang II into Ang(1–7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1–7), an important enzyme for Ang(1–7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus causing the infamous severe acute respiratory syndrome (SARS) in 2003.</p></abstract><kwd-group><title>Keywords</title><kwd>angiotensin converting enzyme</kwd><kwd>angiotensin converting enzyme inhibitor</kwd><kwd>captopril</kwd><kwd>hypertension</kwd><kwd>severe acute respiratory syndrome (SARS)</kwd></kwd-group></article-meta></front><body><p id="p0010"><bold>Additional names/abbreviations:</bold> Angiotensin converting enzyme, dipeptidyl carboxypeptidase I, peptidase P, kininase II, angiotensin I-converting enzyme/ACE; angiotensin converting enzyme 2, peptidyl-dipeptidase A, peptidyl-dipeptidase A/ACE2</p><p id="p0015"><italic>ACE possesses dual actions to convert Ang I to Ang II and degrade bradykinin. The development of ACE inhibitor was the first effective drug for hypertension caused by high renin activity. ACE2 was identified as the receptor for SARS (severe acute respiratory syndrome) coronavirus, which caused the outbreak of an epidemic in 2002</italic>–<italic>2003.</italic></p><sec id="s0010"><title>Discovery</title><p id="p0020">ACE was discovered in the mid-1950s by the observation that dialysis of plasma and kidney extract with water and saline before incubation had produced two separate pressor substances, Ang I and Ang II respectively <xref rid="bib1" ref-type="bibr">[1]</xref>. It was discovered for a second time in 1966 during the characterization of bradykinin (BK) degrading enzyme from kidney and this enzyme was named kininase II; it later was found to be the same enzyme as ACE. ACE2 was discovered in 2000 when two independent research groups cloned homologous ACE that could convert Ang I to Ang(1–9) and yet also is captopril-insensitive <xref rid="bib2" ref-type="bibr">2.</xref>, <xref rid="bib3" ref-type="bibr">3.</xref>.</p></sec><sec id="s0015"><title>Structure</title><sec id="s0020"><title>Structural Features</title><p id="p0025">Two isozymes of ACE are present in mammals: somatic ACE and testis ACE. Somatic ACE possesses two catalytic domains (N- and C-domains) and a C-terminal transmembrane segment (stalk) (<xref rid="f0010" ref-type="fig">Figure 29D.1</xref>). Somatic and testis ACEs in humans contain 1,306 and 665 aa residues, respectively. Testis ACE only possesses one catalytic domain. Both catalytic domains are zinc-metallopeptidase with the active motif HEMGH where the two histidine residues coordinate the zinc ion. The stalk anchors the enzyme on the membrane and is susceptible to be cleaved by shedding enzymes, resulting in plasma ACE activity (<xref rid="f0010" ref-type="fig">Figure 29D.1</xref>). ACE2 is a chimaera protein with a single catalytic domain of ACE, and a C-terminal highly resembling collectrin, which may act as a chaperone protein to deliver other proteins to the brush border membrane.<fig id="f0010"><label>Figure 29D.1</label><caption><p>Schematic diagram showing the functional domains of ACE and ACE2.</p><p>Two extracellular enzymatic domains are present in ACE. An alternative transcript of ACE form testicular ACE which only possess a single enzymatic domain. The stalk anchors the enzyme on the membrane and is suspectible to be cleaved by shedding enzymes, resulting in plasma ACE activity. ACE2 is a chimaera protein with a single catalytic domain of ACE, and a C-terminal highly resemble collectrin, which may act as a chaperone protein to deliver other proteins to the brush border membrane.</p></caption><graphic xlink:href="f29d-01-9780128010280"></graphic></fig></p></sec></sec><sec id="s0025"><title>Synthesis and Release</title><sec id="s0030"><title>Gene and mRNA</title><p id="p0030"><italic>ACE</italic> and <italic>ACE2</italic> genes are located at chromosome 17q23 and Xp22 in humans, respectively. Testis <italic>ACE</italic> is transcribed from the same gene with an alternative transcription starting site on the 13th intron of the <italic>ACE</italic> gene, resulting in only C-domain and stalk segment with a unique additional 67 aa N-terminal sequence in humans. The two catalytic domains are the result of gene/domain duplication and the duplication occurred multiple times in evolution as the cnidarians, crustaceans, insects, and vertebrates possess ACE-like enzymes with one or two catalytic domains. No expression studies so far have been performed for non-mammalian <italic>ACE</italic> and <italic>ACE2</italic>.</p></sec><sec id="s0035"><title>Distribution of mRNA</title><p id="p0035">Somatic <italic>ACE</italic> is expressed in various tissues including blood vessels, kidney, intestine, adrenal gland, liver, and uterus, and is especially abundant in highly vascular organs such as retina and lung. Testis <italic>ACE</italic> is expressed by postmeiotic male germ cells and high-level expression is found in round and elongated spermatids. <italic>ACE2</italic> is expressed in lung, liver, intestine, brain, testis, heart, and kidney.</p></sec><sec id="s0040"><title>Tissue and Plasma Concentrations</title><p id="p0040">Lung possesses the highest amount of ACE and contributes to 0.1% of total protein. Serum ACE levels in humans ranged from 299.3±49 μg/l (DD) to 494.1±88.3 μg/l (II) with heterozygous individuals 392.6±66.8 μg/l <xref rid="bib4" ref-type="bibr">[4]</xref>. (ID: see the section “Pathophysiological Implications” for the genotype definition.) Several enzymatic assays have been developed for the measurement of ACE activity in plasma and tissues and usually involve artificial substrates such as hippuryl-His-Leu or N-[3-(2-furyl)acryloyl]L-phenylalanyl-glycyl-glycine (FAPGG), in combination with captopril inhibition. These methods were developed in mammals but were also extended to other vertebrates including birds, amphibians, and fishes <xref rid="bib5" ref-type="bibr">[5]</xref>. However, these enzymatic methods may be erroneous because the enzyme specificity on the artificial substrates could be different. Lamprey ACE activities in different tissues were measured but captopril failed to decrease the ACE activities, indicating a possible nonspecific enzyme measurement. In amphibian, high captopril-sensitive ACE activities were found in gonad, intestine, kidney, and lung, moderate activities were presented in liver, heart, and skin, and low or negligible activities were observed in plasma, muscle, and erythrocytes.
</p></sec><sec id="s0045"><title>Regulation of Synthesis and Release</title><p id="p0045">Expression of <italic>ACE</italic> is affected by steroids and thyroid hormone, but the details of the regulation are not clear. <italic>ACE</italic> is under promoter regulation by hypoxia-inducing factor 1α (HIF-1α), which upregulates the <italic>ACE</italic> expression under hypoxic conditions, resulting in an increase in Ang II concentration. Under hypoxia, <italic>ACE2</italic> will be downregulated but it was shown that it is indirectly controlled by Ang II, but not HIF-1α <xref rid="bib6" ref-type="bibr">[6]</xref>. Testis <italic>ACE</italic> expression control is highly specific and regulated by a tissue-specific promoter located immediately −59 bp of the transcription start site, which is frequently used in testis-specific overexpression studies. Hypoxia induced by high temperature decreased gill ACE activity but had no effect on kidney in carp. Promoters of <italic>ACE2</italic> from mammals, amphibians, and teleosts drive specific expression in the heart. <italic>Cis</italic>-element search results discovered WGATAR motifs in all putative <italic>ACE2</italic> promoters from different vertebrates, suggesting a possible role of GATA family transcriptional factors in <italic>ACE2</italic> expression regulation.</p></sec></sec><sec id="s0050"><title>Receptors</title><p id="p0050">None.</p><sec id="s0055"><title>Inhibitors</title><p id="p0055">The first ACE inhibitor was a peptide antagonist called SQ 20,881 (GWPRPEIPP) discovered from snake venom but it was not orally active. The snake venom peptides were further studied to produce the first orally active form, captopril, that lowers the blood pressure of essential hypertensive patients <xref rid="bib7" ref-type="bibr">[7]</xref>. The most common side effects of captopril are cough, skin rash, and loss of taste, and therefore derivatives such as enalapril, lisinopril, and ramipril were developed with fewer side effects. After the discovery of N- and C-domains of ACE, specific domain inhibitors were developed to increase specificity. Ang I is mainly hydrolyzed by the C-domain <italic>in vivo</italic> but BK is hydrolyzed by both domains. By developing a C-domain selective inhibitor (RXPA380) some degradation of BK by the N-domain would be permitted and this degradation could be enough to prevent accumulation of excess BK causing angioedema <xref rid="bib8" ref-type="bibr">[8]</xref>.</p></sec></sec><sec id="s0060"><title>Biological Functions</title><sec id="s0065"><title>Target Cells/Tissues and Functions</title><p id="p0060">The well-known function of ACE is the conversion of Ang I to Ang II and degradation of BK, which all play an important role in controlling blood pressure. ACE also acts on other natural substrates including encephalin, neurotensin, and substance P. Besides being involved in blood pressure control, ACE possesses widespread functions including renal development, male fertility, hematopoiesis, erythropoiesis, myelopoiesis, and immune responses <xref rid="bib1" ref-type="bibr">[1]</xref>. ACE2 can convert Ang II to Ang(1–7), thereby reducing the concentration of Ang II and increasing that of Ang(1–7). ACE2 can also convert Ang I to Ang(1–9), which is subsequently converted into Ang(1–7) by ACE. The high expression of ACE2 favors the balance of Ang(1–7) over Ang II, which accounts for the cardioprotective role of ACE2 via the Ang(1–7)/Mas signaling pathway <xref rid="bib9" ref-type="bibr">[9]</xref>.</p></sec><sec id="s0070"><title>Phenotype in Gene-Modified Animals</title><p id="p0065">ACE-knockout mice display normal blood pressure under normal conditions, but are sensitive to changes in blood pressure such as exercise. ACE-knockout also affects renal function, renal development, serum and urine electrolyte composition, haematocrit, and male reproductive capacity
<xref rid="bib10" ref-type="bibr">[10]</xref>. Deficiency in testis ACE affects male fertility but its exact role is still not clear. Although mice with testis ACE deficiency mate normally and their sperm quantity and motility are no different from those of wild-type mice, the survival of sperm in the oviduct and fertilization rate are highly reduced <xref rid="bib1" ref-type="bibr">[1]</xref>. Overexpression of <italic>ACE2</italic> in hypertensive models, but not in normotensive animals, reduced blood pressure. ACE2-knockout mice displayed progressive cardiac dysfunction resembling that of long-term hypoxia after coronary artery disease or bypass surgery in human, which could be reversed by concurrent ACE-knockout. It was suggested that the cardioprotective function of ACE2 is to counterbalance the effects of ACE.</p></sec></sec><sec id="s0075"><title>Pathophysiological Implications</title><sec id="s0080"><title>Clinical Implications</title><p id="p0070">Inclusion (II) or deletion (DD) of 287 bp Alu repeats in the 16th intron affects the human plasma ACE levels and the DD genotype was more frequently found in patients with myocardial infarction but no convincing evidence was available on the association of the DD genotype with hypertension <xref rid="bib4" ref-type="bibr">[4]</xref>. ACE2 was identified as the receptor for SARS (severe acute respiratory syndrome) coronavirus. SARS virus binding downregulates the cellular expression of <italic>ACE2</italic>, and the binding induces clathrin-dependent internalization of virus/receptor (SARS/ACE2) complex. Not only has ACE2 facilitated the invasion of SARS virus for rapid replication, but also ACE2 is depleted from the cell membrane and therefore the damaging effects of Ang II are enhanced, resulting in acute deterioration of lung tissues.</p></sec><sec id="s0085"><title>Use for Diagnosis and Treatment</title><p id="p0075">ACE has been the target of hypertension control since the 1970s. ACE inhibitors are prescribed as the sole or combinational treatment of high blood pressure, for the dual effects of lowering Ang II and slowing down BK degradation. 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