Metabolism of angiotensinogen to angiotensins (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Metabolism of Angiotensinogen to Angiotensins" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">Angiotensinogen, a prohormone, is synthesized and secreted mainly by the liver but also from other tissues (reviewed in Fyhrquist and Saijonmaa 2008, Cat and Touyz 2011). Renin, an aspartyl protease specific for angiotensinogen, is secreted into the bloodstream by juxtaglomerular cells of the kidney in response to a drop in blood pressure. Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Circulating renin can also bind the membrane-localized (pro)renin receptor (ATP6AP2) which increases its catalytic activity. After cleavage of angiotensinogen to angiotensin I by renin, two C-terminal amino acid residues of angiotensin I are removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion.&lt;br&gt;More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified (reviewed in Kramkowski et al. 2006, Kumar et al. 2007, Fyhrquist and Saijonmaa 2008, Becari et al. 2011). Chymase, cathepsin G, and cathepsin X (cathepsin Z) can each cleave angiotensin I to yield angiotensin II. Angiotensin-converting enzyme 2 (ACE2) cleaves 1 amino acid residue from angiotensin I (angiotensin-(1-10)) to yield angiotensin-(1-9), which can be cleaved by ACE to yield angiotensin-(1-7). ACE2 can also cleave angiotensin II to yield angiotensin-(1-7). Neprilysin can cleave either angiotensin-(1-9) or angiotensin I to yield angiotensin-(1-7). Angiotensin-(1-7) binds the MAS receptor (MAS1, MAS proto-oncogene) and, interestingly, produces effects opposite to those produced by angiotensin II.&lt;br&gt;Aminopeptidase A (APA, ENPEP) cleaves angiotensin II to yield angiotensin III (angiotensin-(2-8)), which is then cleaved by aminopeptidase N (APN, ANPEP) yielding angiotensin IV (angiotensin-(3-8)). Angiotensin IV binds the AT4 receptor (AT4R, IRAP, LNPEP, oxytocinase).&lt;br&gt;Inhibitors of renin (e.g. aliskiren) and ACE (e.g. lisinopril, ramipril) are currently used to treat hypertension (reviewed in Gerc et al. 2009, Verdecchia et al. 2010, Alreja and Joseph 2011). View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=2022377 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 2022377</Comment> <Comment Source="Reactome-version">Reactome version: 62</Comment> <Comment Source="Reactome Author">Reactome Author: May, Bruce</Comment> <BiopaxRef>e6f</BiopaxRef> <BiopaxRef>c65</BiopaxRef> <BiopaxRef>a03</BiopaxRef> <BiopaxRef>eb3</BiopaxRef> <BiopaxRef>f67</BiopaxRef> <BiopaxRef>d7d</BiopaxRef> <BiopaxRef>dc5</BiopaxRef> <BiopaxRef>a5c</BiopaxRef> <BiopaxRef>f01</BiopaxRef> <BiopaxRef>ed3</BiopaxRef> <BiopaxRef>aa3</BiopaxRef> <Attribute Key="reactome_id" Value="2022377" /> <Graphics BoardWidth="1276.0" BoardHeight="1631.0" /> <DataNode TextLabel="ramiprilat" GraphId="a2e10" Type="Metabolite"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="703.5" CenterY="433.0" Width="73.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> 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TextLabel="CPB2 " GraphId="d5a8f" Type="Protein" GroupRef="c360d"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-3229246" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1511.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96IY4" /> </DataNode> <DataNode TextLabel="AGT(35-41)" GraphId="d605f" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="147.5" CenterY="450.0" Width="71.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01019" /> </DataNode> <DataNode TextLabel="ACE(30-1306)" GraphId="d61bd" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="363.0" CenterY="380.5" Width="110.0" Height="27.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P12821" /> 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/> <Point X="785.0" Y="419.0" GraphRef="f8f71" RelX="-26.0" RelY="-1.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="a5225"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="840.0" Y="359.0" GraphRef="e054f" RelX="-0.010309278350515464" RelY="-1.0" /> <Point X="785.0" Y="419.0" GraphRef="c0069" RelX="-26.0" RelY="-1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="a5c03"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="490.0" Y="537.0" GraphRef="f3075" RelX="1.0" RelY="-0.04" /> <Point X="829.0" Y="732.0" GraphRef="b5f25" RelX="-34.0" RelY="-81.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022379" /> </Interaction> <Interaction GraphId="a64a5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="323.0" Y="261.0" GraphRef="cd3a1" RelX="-0.005649717514124294" RelY="-1.0" /> <Point X="409.0" Y="227.0" GraphRef="bcac1" RelX="-190.5" RelY="56.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022403" /> </Interaction> <Interaction GraphId="a67f5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="418.0" Y="380.0" GraphRef="d61bd" RelX="1.0" RelY="-0.037037037037037035" /> <Point X="974.0" Y="770.0" GraphRef="f185e" RelX="0.5" RelY="-72.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022398" /> </Interaction> <Interaction GraphId="a6913"> <Comment Source="Reactome">Neprilysin hydrolyzes angiotensin-(1-10) (angiotensin I) directly to angiotensin-(1-7) (Rice et al. 2004).</Comment> <BiopaxRef>ced</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1246.0" Y="244.0" /> <Point X="919.0" Y="951.0" /> <Anchor Position="0.0" Shape="None" GraphId="ed571" /> <Anchor Position="0.99" Shape="None" GraphId="d6d03" /> <Anchor Position="0.5" Shape="None" GraphId="f44ff" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022396" /> </Interaction> <Interaction GraphId="a6c18"> <Comment Source="Reactome">Aminopeptidase N (APN, ANPEP, aminopeptidase M, alanyl aminopeptidase) hydrolyzes angiotensin-(2-8) (angiotensin III) to yield angiotensin-(3-8) (angiotensin IV) (see the positive control reactions in Diaz-Perales et al. 2005). Aminopeptidase O (AOPEP) also hydrolyzes angiotensin-(2-8) to angiotensin-(3-8) in vitro (Diaz-Perales et al. 2005) but AOPEP is located in the nucleolus in vivo (Axton et al. 2008) and angiotensin-(2-8) has not been observed in the nucleus.</Comment> <BiopaxRef>d2f</BiopaxRef> <BiopaxRef>a47</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="615.0" Y="875.0" /> <Point X="615.0" Y="950.0" /> <Anchor Position="0.0" Shape="None" GraphId="f9297" /> <Anchor Position="0.99" Shape="None" GraphId="a1b83" /> <Anchor Position="0.5" Shape="None" GraphId="e2bf7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022393" /> </Interaction> <Interaction GraphId="a9918"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="857.0" Y="589.0" GraphRef="e0217" RelX="-1.4700000000000273" RelY="2.6099999999999" /> <Point X="835.0" Y="592.0" GraphRef="db67b" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref 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Y="733.0" GraphRef="b818a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022398" /> </Interaction> <Interaction GraphId="b7b9e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="481.0" Y="662.0" GraphRef="cefd0" RelX="0.9819819819819819" RelY="0.0" /> <Point X="714.0" Y="721.0" GraphRef="a4854" RelX="14.0" RelY="-4.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022399" /> </Interaction> <Interaction GraphId="b8ce2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="693.0" Y="383.0" GraphRef="a2e10" RelX="-0.2876712328767123" RelY="-3.3333333333333335" /> <Point X="561.0" Y="379.0" GraphRef="a9058" RelX="-193.5" RelY="-36.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="b9556"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="407.0" Y="127.0" GraphRef="fe7eb" RelX="-1.0" RelY="-0.03225806451612903" /> <Point X="527.0" Y="176.0" GraphRef="b11fe" RelX="-96.0" RelY="38.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065357" /> </Interaction> <Interaction GraphId="b96da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="974.0" Y="712.0" GraphRef="dab74" RelX="-1.0" RelY="0.0" /> <Point X="936.0" Y="718.0" GraphRef="b4ff2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022368" /> </Interaction> <Interaction GraphId="b9742"> <Comment Source="Reactome">Renin in the bloodstream hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I). Renin is produced in the juxtaglomerular cells of the kidney in response to reduced blood pressure. Aliskiren, a drug used clinically to treat hypertension, inhibits this reaction (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).</Comment> <BiopaxRef>a42</BiopaxRef> <BiopaxRef>c0f</BiopaxRef> <BiopaxRef>b3f</BiopaxRef> <BiopaxRef>c50</BiopaxRef> <BiopaxRef>bb9</BiopaxRef> <BiopaxRef>dc5</BiopaxRef> <BiopaxRef>ec2</BiopaxRef> <BiopaxRef>f83</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="329.0" Y="111.0" /> <Point X="881.0" Y="92.0" /> <Anchor Position="0.0" Shape="None" GraphId="bec40" /> <Anchor Position="0.99" Shape="None" GraphId="fbc91" /> <Anchor Position="0.5" Shape="None" GraphId="c6cc9" /> <Anchor Position="0.5" Shape="None" GraphId="b2689" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022412" /> </Interaction> <Interaction GraphId="badac"> <Comment Source="Reactome">The binding of prorenin to the (pro)renin receptor activates the protease activity of prorenin, which can then hydrolyze angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Prorenin is inactive when not bound to the (pro)renin receptor. Aliskiren, a drug used clinically to treat hypertension, inhibits the cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).</Comment> <BiopaxRef>bb9</BiopaxRef> <BiopaxRef>ec2</BiopaxRef> <BiopaxRef>f83</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="365.0" Y="168.0" /> <Point X="881.0" Y="107.0" /> <Anchor Position="0.0" Shape="None" GraphId="ed4a4" /> <Anchor Position="0.99" Shape="None" GraphId="cc4d1" /> <Anchor Position="0.5" Shape="None" GraphId="c35ec" /> <Anchor Position="0.5" Shape="None" GraphId="b11fe" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065357" /> </Interaction> <Interaction GraphId="bbfbe"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="183.0" Y="62.0" GraphRef="eb5e9" RelX="0.984" RelY="0.0" /> <Point X="329.0" Y="111.0" GraphRef="bec40" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022412" /> </Interaction> <Interaction GraphId="be17f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1042.0" Y="624.0" GraphRef="b67d0" RelX="0.009999999999990905" RelY="3.4700000000000273" /> <Point X="1042.0" Y="627.0" GraphRef="d6d2f" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022378" /> </Interaction> <Interaction GraphId="be9a1"> <Comment Source="Reactome">Renin bound to the (pro)renin receptor (ATP6AP2) hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Binding to the (pro)renin receptor increases the catalytic efficiency of renin 4-fold (Nguyen et al. 2002). Aliskiren, a drug used clinically to treat hypertension, inhibits cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).</Comment> <BiopaxRef>bb9</BiopaxRef> <BiopaxRef>ec2</BiopaxRef> <BiopaxRef>f83</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="315.0" Y="229.0" /> <Point X="884.0" Y="113.0" /> <Anchor Position="0.0" Shape="None" GraphId="fab36" /> <Anchor Position="0.99" Shape="None" GraphId="dd031" /> <Anchor Position="0.5" Shape="None" GraphId="bcac1" /> <Anchor Position="0.5" Shape="None" GraphId="f0771" /> <Anchor Position="0.5" Shape="None" GraphId="c8388" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022403" /> </Interaction> <Interaction GraphId="bfb74"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="983.0" Y="316.0" GraphRef="a6cfe" RelX="1.0" RelY="0.0" /> <Point X="1004.0" Y="328.0" GraphRef="da5c4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022383" /> </Interaction> <Interaction GraphId="bfe6a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="146.0" Y="590.0" GraphRef="f3e66" RelX="0.0" RelY="0.7000000000000455" /> <Point X="128.0" Y="635.0" GraphRef="d3130" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8851929" /> </Interaction> <Interaction GraphId="c0940"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="724.0" Y="398.0" GraphRef="f374f" RelX="0.20588235294117646" RelY="5.0" /> <Point X="785.0" Y="419.0" GraphRef="f8f71" RelX="-26.0" RelY="-1.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="c0f31"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="418.0" Y="380.0" GraphRef="d61bd" RelX="1.0" RelY="-0.037037037037037035" /> <Point X="561.0" Y="379.0" GraphRef="e67f8" RelX="-193.5" RelY="-36.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="c136b"> <Comment Source="Reactome">Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Ehlers and Kirsch 1988). ACE is found at the plasma membrane of endothelial cells. This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999).</Comment> <BiopaxRef>bcc</BiopaxRef> <BiopaxRef>e4b</BiopaxRef> <BiopaxRef>fd6</BiopaxRef> <BiopaxRef>a4d</BiopaxRef> <BiopaxRef>de0</BiopaxRef> <BiopaxRef>baf</BiopaxRef> <BiopaxRef>fc3</BiopaxRef> <BiopaxRef>d65</BiopaxRef> <BiopaxRef>ea7</BiopaxRef> <BiopaxRef>c2d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="692.0" Y="241.0" /> <Point X="817.0" Y="589.0" /> <Anchor Position="0.0" Shape="None" GraphId="dcc00" /> <Anchor Position="0.99" Shape="None" GraphId="eec8d" /> <Anchor Position="0.5" Shape="None" GraphId="e67f8" /> <Anchor Position="0.5" Shape="None" GraphId="a9058" /> <Anchor Position="0.5" Shape="None" GraphId="c62b9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="c17cb"> <Comment Source="Reactome">Chymase hydrolyzes angiotensin-(1-10) (angiotensin) to yield angiotensin-(1-8) (angiotensin II) at a higher rate than does angiotensin-converting enzyme (Reilly et al. 1982, Urata et al. 1990, Caughey et al. 2000, Richard et al. 2001).</Comment> <BiopaxRef>ec4</BiopaxRef> <BiopaxRef>d27</BiopaxRef> <BiopaxRef>ca1</BiopaxRef> <BiopaxRef>a39</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1004.0" Y="328.0" /> <Point X="857.0" Y="589.0" /> <Anchor Position="0.0" Shape="None" GraphId="da5c4" /> <Anchor Position="0.99" Shape="None" GraphId="e0217" /> <Anchor Position="0.5" Shape="None" GraphId="cfe04" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022383" /> </Interaction> <Interaction GraphId="c2846"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1092.0" Y="264.0" GraphRef="cec83" RelX="0.9512195121951219" RelY="0.0" /> <Point X="1108.0" Y="252.0" GraphRef="a018a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2028294" /> </Interaction> <Interaction GraphId="c29cc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="328.0" Y="176.0" GraphRef="ad189" RelX="0.9534883720930233" RelY="0.0" /> <Point X="365.0" Y="168.0" GraphRef="ed4a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065357" /> </Interaction> <Interaction GraphId="c3254"> <Comment Source="Reactome">Aminopeptidase O (AOPEP, AP-O) is a member of the M1 family of zinc metallopeptidases or gluzincins. AOPEP contains a large catalytic gluzincin domain which has the archetypal metalloprotease zinc-binding site ending in a family-specific Glu residue (HEXXHX[18]E) typical to this family. AOPEP is able to catalyse the hydrolsis of an arginine residue (L-Arg) from angiotensin III (AGT(35-41)) to form angiotensin IV (AGT(36-41)), a bioactive peptide of the renin-angiotensin pathway. AOPEP does not contain a recognisable signal sequence or type II transmembrane domain, indicating that it likely belongs to the cytoplasmic subfamily of gluzincins (Diaz-Perales et al. 2005). AOPEP mRNA transcripts are predominantly detected in the pancreas, placenta, liver, testis, and heart. Expression of the AOPEP in heart and testis could suggest involvement in the regulation of cardiac and male reproductive physiology (Diaz-Perales et al. 2005).</Comment> <BiopaxRef>d2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="146.0" Y="520.0" /> <Point X="146.0" Y="590.0" /> <Anchor Position="0.0" Shape="None" GraphId="efb6d" /> <Anchor Position="0.99" Shape="None" GraphId="f3e66" /> <Anchor Position="0.5" Shape="None" GraphId="b5234" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8851929" /> </Interaction> <Interaction GraphId="c46e5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="946.0" Y="110.0" GraphRef="cba1f" RelX="-0.008" RelY="1.0" /> <Point X="902.0" Y="317.0" GraphRef="cf7f6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022381" /> </Interaction> <Interaction GraphId="c623d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1052.0" Y="264.0" GraphRef="cec83" RelX="-1.0" RelY="0.0" /> <Point X="1041.0" Y="277.0" GraphRef="c213a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022378" /> </Interaction> <Interaction GraphId="c7118"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="764.0" Y="250.0" GraphRef="b4620" RelX="0.9428571428571428" RelY="0.0" /> <Point X="785.0" Y="419.0" GraphRef="aeadd" RelX="-26.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="c74bf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="979.0" Y="642.0" GraphRef="d6d2f" RelX="-1.0" RelY="-0.03225806451612903" /> <Point X="936.0" Y="718.0" GraphRef="b4ff2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022368" /> </Interaction> <Interaction GraphId="c84fd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="469.0" Y="884.0" GraphRef="d1780" RelX="1.0" RelY="-0.037037037037037035" /> <Point X="614.0" Y="904.0" GraphRef="e2bf7" RelX="-1.0" RelY="-8.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022393" /> </Interaction> <Interaction GraphId="c8b61"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1008.0" Y="95.0" GraphRef="cba1f" RelX="0.984" RelY="0.0" /> <Point X="1246.0" Y="244.0" GraphRef="ed571" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022396" /> </Interaction> <Interaction GraphId="cb97a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="693.0" Y="383.0" GraphRef="cc32c" RelX="0.0" RelY="-1.0" /> <Point X="561.0" Y="379.0" GraphRef="a9058" RelX="-193.5" RelY="-36.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="cbd4b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="908.0" Y="951.0" GraphRef="b171c" RelX="-1.3099999999999454" RelY="2.1800000000000637" /> <Point X="903.0" Y="954.0" GraphRef="babad" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022398" /> </Interaction> <Interaction GraphId="cc9d0"> <Comment Source="Reactome">Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-9) (Donoghue et al. 2000, Tipnis et al. 2000, Vickers et al. 2002, Rice t al. 2004). The activity of ACE2 on angiotensin I is weak (Rice et al. 2004), being 400-fold lower than the activity of ACE2 on angiotensin II (Vickers et al. 2002).</Comment> <BiopaxRef>a6d</BiopaxRef> <BiopaxRef>b54</BiopaxRef> <BiopaxRef>df9</BiopaxRef> <BiopaxRef>ced</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1041.0" Y="277.0" /> <Point X="1042.0" Y="624.0" /> <Anchor Position="0.0" Shape="None" GraphId="c213a" /> <Anchor Position="0.99" Shape="None" GraphId="b67d0" /> <Anchor Position="0.5" Shape="None" GraphId="b81f7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022378" /> </Interaction> <Interaction GraphId="cd0b0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="323.0" Y="261.0" GraphRef="cd3a1" RelX="-0.005649717514124294" RelY="-1.0" /> <Point X="409.0" Y="227.0" GraphRef="c8388" RelX="-190.5" RelY="56.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022403" /> </Interaction> <Interaction GraphId="cea81"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="686.0" Y="810.0" GraphRef="e1742" RelX="-0.2799999999999727" RelY="1.7000000000000455" /> <Point X="682.0" Y="813.0" GraphRef="d85ba" RelX="-0.008849557522123894" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022399" /> </Interaction> <Interaction GraphId="d068a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="881.0" Y="92.0" GraphRef="fbc91" RelX="5.519999999999982" RelY="-0.18999999999999773" /> <Point X="884.0" Y="95.0" GraphRef="cba1f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022412" /> </Interaction> <Interaction GraphId="d25ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="818.0" Y="243.0" GraphRef="df30c" RelX="-1.0" RelY="0.0" /> <Point X="791.0" Y="251.0" GraphRef="c8136" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="d380e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="919.0" Y="951.0" GraphRef="d6d03" RelX="-3.269999999999982" RelY="7.07000000000005" /> <Point X="903.0" Y="954.0" GraphRef="babad" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022396" /> </Interaction> <Interaction GraphId="d3f02"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="946.0" Y="110.0" GraphRef="cba1f" RelX="-0.008" RelY="1.0" /> <Point X="1004.0" Y="328.0" GraphRef="da5c4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022383" /> </Interaction> <Interaction GraphId="d545b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="884.0" Y="113.0" GraphRef="dd031" RelX="5.689999999999941" RelY="-1.1599999999999966" /> <Point X="884.0" Y="95.0" GraphRef="cba1f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022403" /> </Interaction> <Interaction GraphId="d554d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="123.0" Y="480.0" GraphRef="b82f1" RelX="1.0" RelY="0.0" /> <Point X="146.0" Y="520.0" GraphRef="efb6d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8851929" /> </Interaction> <Interaction GraphId="d882f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1112.0" Y="423.0" GraphRef="f504e" RelX="-1.0" RelY="0.0" /> <Point X="1075.0" Y="422.0" GraphRef="d1b59" RelX="-1.0" RelY="-16.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2028294" /> </Interaction> <Interaction GraphId="d8c1e"> <Comment Source="Reactome">Secreted angiotensin-converting enzyme (ACE) cleaves 2 amino acid residues from the C-terminus of angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Wei et al. 1991). This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999). ACE is secreted ("shed") from membranes of endothelial cells by cleavage in the C-terminal region that removes the membrane anchor.</Comment> <BiopaxRef>fd6</BiopaxRef> <BiopaxRef>e4b</BiopaxRef> <BiopaxRef>a4d</BiopaxRef> <BiopaxRef>de0</BiopaxRef> <BiopaxRef>baf</BiopaxRef> <BiopaxRef>fc3</BiopaxRef> <BiopaxRef>d65</BiopaxRef> <BiopaxRef>ea7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="791.0" Y="251.0" /> <Point X="831.0" Y="589.0" /> <Anchor Position="0.0" Shape="None" GraphId="c8136" /> <Anchor Position="0.99" Shape="None" GraphId="ba47c" /> <Anchor Position="0.5" Shape="None" GraphId="c0069" /> <Anchor Position="0.5" Shape="None" GraphId="f8f71" /> <Anchor Position="0.5" Shape="None" GraphId="aeadd" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="da743"> <Comment Source="Reactome">Cathepsin Z (cathepsin X) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Nagler et al. 2010).</Comment> <BiopaxRef>e6c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="902.0" Y="317.0" /> <Point X="842.0" Y="589.0" /> <Anchor Position="0.0" Shape="None" GraphId="cf7f6" /> <Anchor Position="0.99" Shape="None" GraphId="f8702" /> <Anchor Position="0.5" Shape="None" GraphId="fbfc9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022381" /> </Interaction> <Interaction GraphId="dba28"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="183.0" Y="62.0" GraphRef="eb5e9" RelX="0.984" RelY="0.0" /> <Point X="365.0" Y="168.0" GraphRef="ed4a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065357" /> </Interaction> <Interaction GraphId="dbdb5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="407.0" Y="127.0" GraphRef="fe7eb" RelX="-1.0" RelY="-0.03225806451612903" /> <Point X="409.0" Y="227.0" GraphRef="f0771" RelX="-190.5" RelY="56.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022403" /> </Interaction> <Interaction GraphId="dc14f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="724.0" Y="398.0" GraphRef="a2e10" RelX="0.5616438356164384" RelY="-2.3333333333333335" /> <Point X="785.0" Y="419.0" GraphRef="f8f71" RelX="-26.0" RelY="-1.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065355" /> </Interaction> <Interaction GraphId="dc1bc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="693.0" Y="383.0" GraphRef="d76da" RelX="-0.07692307692307693" RelY="1.4666666666666666" /> <Point X="561.0" Y="379.0" GraphRef="a9058" RelX="-193.5" RelY="-36.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="dc79a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="615.0" Y="950.0" GraphRef="a1b83" RelX="0.0" RelY="0.75" /> <Point X="616.0" Y="953.0" GraphRef="f56f8" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022393" /> </Interaction> <Interaction GraphId="dd75b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="817.0" Y="589.0" GraphRef="eec8d" RelX="1.25" RelY="3.480000000000018" /> <Point X="835.0" Y="592.0" GraphRef="db67b" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2022405" /> </Interaction> <Interaction GraphId="ddceb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="881.0" Y="107.0" GraphRef="cc4d1" RelX="5.159999999999968" RelY="-0.6099999999999994" /> <Point X="884.0" Y="95.0" GraphRef="cba1f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2065357" /> </Interaction> <Interaction GraphId="df182"> <Graphics ConnectorType="Segmented" ZOrder="12288" 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Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Campbell EJ, Silverman EK, Campbell MA.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="a03"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">17229979</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The physiological significance of the alternative pathways of angiotensin II production.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kramkowski K, Mogielnicki A, Buczko W.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c65"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21499495</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Renin and cardiovascular disease: Worn-out path, or new direction.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Alreja G, Joseph J.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="baf"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">3017438</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rapid affinity chromatographic purification of human lung and kidney angiotensin-converting enzyme with the novel N-carboxyalkyl dipeptide inhibitor N-[1(S)-carboxy-5-aminopentyl]glycylglycine.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ehlers MR, Maeder DL, Kirsch RE.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b54"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10924499</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">A human homolog of angiotensin-converting enzyme. 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