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Entry: ACE_RABIT
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ID   ACE_RABIT               Reviewed;        1310 AA.
AC   P12822; O02852; P22968;
DT   01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1997, sequence version 3.
DT   12-SEP-2018, entry version 136.
DE   RecName: Full=Angiotensin-converting enzyme;
DE            Short=ACE;
DE            EC=3.2.1.-;
DE            EC=3.4.15.1;
DE   AltName: Full=Dipeptidyl carboxypeptidase I;
DE   AltName: Full=Kininase II;
DE   AltName: CD_antigen=CD143;
DE   Contains:
DE     RecName: Full=Angiotensin-converting enzyme, soluble form;
DE   Flags: Precursor;
GN   Name=ACE; Synonyms=DCP1;
OS   Oryctolagus cuniculus (Rabbit).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae;
OC   Oryctolagus.
OX   NCBI_TaxID=9986;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SOMATIC).
RC   TISSUE=Lung;
RX   PubMed=1311831; DOI=10.1093/nar/20.4.683;
RA   Thekkumkara T.J., Livingston W. III, Kumar R.S., Sen G.C.;
RT   "Use of alternative polyadenylation sites for tissue-specific
RT   transcription of two angiotensin-converting enzyme mRNAs.";
RL   Nucleic Acids Res. 20:683-687(1992).
RN   [2]
RP   SEQUENCE REVISION.
RA   Sen G.C.;
RL   Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TESTIS-SPECIFIC).
RC   STRAIN=New Zealand white; TISSUE=Testis;
RX   PubMed=2550457;
RA   Kumar R.S., Kusari J., Roy S.N., Soffer R.L., Sen G.C.;
RT   "Structure of testicular angiotensin-converting enzyme. A segmental
RT   mosaic isozyme.";
RL   J. Biol. Chem. 264:16754-16758(1989).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-88, AND ALTERNATIVE SPLICING.
RC   TISSUE=Liver;
RX   PubMed=1847388;
RA   Kumar R.S., Thekkumkara T.J., Sen G.C.;
RT   "The mRNAs encoding the two angiotensin-converting isozymes are
RT   transcribed from the same gene by a tissue-specific choice of
RT   alternative transcription initiation sites.";
RL   J. Biol. Chem. 266:3854-3862(1991).
RN   [5]
RP   PROTEIN SEQUENCE OF 34-44 AND 755-758.
RX   PubMed=6291514; DOI=10.1016/0006-291X(82)90634-9;
RA   Iwata K., Lai C.Y., El-Dorry H.A., Soffer R.L.;
RT   "The NH2- and COOH-terminal sequences of the angiotensin-converting
RT   enzyme isozymes from rabbit lung and testis.";
RL   Biochem. Biophys. Res. Commun. 107:1097-1103(1982).
RN   [6]
RP   PROTEIN SEQUENCE OF 34-55.
RC   TISSUE=Lung;
RX   PubMed=6314908; DOI=10.1016/0003-9861(83)90362-4;
RA   Iwata K., Blacher R., Soffer R.L., Lai C.Y.;
RT   "Rabbit pulmonary angiotensin-converting enzyme: the NH2-terminal
RT   fragment with enzymatic activity and its formation from the native
RT   enzyme by NH4OH treatment.";
RL   Arch. Biochem. Biophys. 227:188-201(1983).
RN   [7]
RP   PROTEIN SEQUENCE OF 34-55, AND GLYCOSYLATION.
RX   PubMed=1654880; DOI=10.1042/bj2780375;
RA   Kirley T.L.;
RT   "The Mg(2+)-ATPase of rabbit skeletal-muscle transverse tubule is a
RT   highly glycosylated multiple-subunit enzyme.";
RL   Biochem. J. 278:375-380(1991).
RN   [8]
RP   NUCLEOTIDE SEQUENCE OF 646-746.
RX   PubMed=1705622;
RA   Sen G.C., Thekkumkara T.J., Kumar R.S.;
RT   "Angiotensin-converting enzyme: structural relationship of the
RT   testicular and the pulmonary forms.";
RL   J. Cardiovasc. Pharmacol. 16:S14-S18(1990).
RN   [9]
RP   PROTEIN SEQUENCE OF 727-733 AND 809-815.
RX   PubMed=2176870; DOI=10.1021/bi00498a011;
RA   Chen Y.N., Riordan J.F.;
RT   "Identification of essential tyrosine and lysine residues in
RT   angiotensin converting enzyme: evidence for a single active site.";
RL   Biochemistry 29:10493-10498(1990).
RN   [10]
RP   PROTEIN SEQUENCE OF 1237-1259, AND CLEAVAGE SITE.
RX   PubMed=8294466;
RA   Ramchandran R., Sen G.C., Misono K., Sen I.;
RT   "Regulated cleavage-secretion of the membrane-bound angiotensin-
RT   converting enzyme.";
RL   J. Biol. Chem. 269:2125-2130(1994).
RN   [11]
RP   MUTAGENESIS OF LYS-727 AND TYR-809, ACTIVITY REGULATION, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=7902354;
RA   Sen I., Kasturi S., Abdul-Jabbar M., Sen G.C.;
RT   "Mutations in two specific residues of testicular angiotensin-
RT   converting enzyme change its catalytic properties.";
RL   J. Biol. Chem. 268:25748-25754(1993).
CC   -!- FUNCTION: Converts angiotensin I to angiotensin II by release of
CC       the terminal His-Leu, this results in an increase of the
CC       vasoconstrictor activity of angiotensin. Also able to inactivate
CC       bradykinin, a potent vasodilator. Has also a glycosidase activity
CC       which releases GPI-anchored proteins from the membrane by cleaving
CC       the mannose linkage in the GPI moiety (By similarity).
CC       {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY: Release of a C-terminal dipeptide,
CC       oligopeptide-|-Xaa-Yaa, when Xaa is not Pro, and Yaa is neither
CC       Asp nor Glu. Thus, conversion of angiotensin I to angiotensin II,
CC       with increase in vasoconstrictor activity, but no action on
CC       angiotensin II.
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 2 Zn(2+) ions per subunit. Isoform Testis-specific only
CC       binds 1 Zn(2+) ion per subunit. {ECO:0000250};
CC   -!- COFACTOR:
CC       Name=chloride; Xref=ChEBI:CHEBI:17996; Evidence={ECO:0000250};
CC       Note=Binds 3 chloride ions per subunit. {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Strongly activated by chloride. Specifically
CC       inhibited by lisinopril. {ECO:0000269|PubMed:7902354}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.6 mM for Hip-His-Leu {ECO:0000269|PubMed:7902354};
CC         KM=0.09 mM for angiotensin I {ECO:0000269|PubMed:7902354};
CC   -!- SUBCELLULAR LOCATION: Angiotensin-converting enzyme, soluble form:
CC       Secreted {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass
CC       type I membrane protein {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC       Note=Detected in both cell membrane and cytoplasm in neurons.
CC       {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=Somatic;
CC         IsoId=P12822-1; Sequence=Displayed;
CC       Name=Testis-specific; Synonyms=ACE-T;
CC         IsoId=P12822-2, P22968-1;
CC         Sequence=VSP_037644, VSP_037645;
CC   -!- TISSUE SPECIFICITY: Testis-specific isoform is expressed in
CC       spermatocytes, adult testis.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:1654880}.
CC   -!- PTM: Phosphorylated by CK2 on Ser-1303; which allows membrane
CC       retention. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the peptidase M2 family. {ECO:0000305}.
DR   EMBL; X62551; CAA44428.1; -; mRNA.
DR   EMBL; J05041; AAA31153.1; -; mRNA.
DR   EMBL; M58579; AAA31151.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; M58580; AAA31152.1; -; Genomic_DNA.
DR   PIR; A34402; A34402.
DR   PIR; S35484; S35484.
DR   RefSeq; NP_001075864.1; NM_001082395.1. [P12822-1]
DR   RefSeq; NP_001164540.1; NM_001171069.1. [P12822-2]
DR   UniGene; Ocu.1824; -.
DR   ProteinModelPortal; P12822; -.
DR   SMR; P12822; -.
DR   STRING; 9986.ENSOCUP00000016378; -.
DR   BindingDB; P12822; -.
DR   ChEMBL; CHEMBL4074; -.
DR   MEROPS; M02.001; -.
DR   PRIDE; P12822; -.
DR   GeneID; 100009274; -.
DR   KEGG; ocu:100009274; -.
DR   CTD; 1636; -.
DR   eggNOG; KOG3690; Eukaryota.
DR   eggNOG; ENOG410XPJ3; LUCA.
DR   HOGENOM; HOG000007838; -.
DR   HOVERGEN; HBG000264; -.
DR   InParanoid; P12822; -.
DR   KO; K01283; -.
DR   SABIO-RK; P12822; -.
DR   Proteomes; UP000001811; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0004180; F:carboxypeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008241; F:peptidyl-dipeptidase activity; IEA:InterPro.
DR   CDD; cd06461; M2_ACE; 2.
DR   InterPro; IPR001548; Peptidase_M2.
DR   PANTHER; PTHR10514; PTHR10514; 2.
DR   Pfam; PF01401; Peptidase_M2; 2.
DR   PRINTS; PR00791; PEPDIPTASEA.
DR   PROSITE; PS00142; ZINC_PROTEASE; 2.
PE   1: Evidence at protein level;
KW   Alternative splicing; Carboxypeptidase; Cell membrane;
KW   Complete proteome; Cytoplasm; Direct protein sequencing;
KW   Disulfide bond; Glycoprotein; Hydrolase; Membrane; Metal-binding;
KW   Metalloprotease; Phosphoprotein; Protease; Reference proteome; Repeat;
KW   Secreted; Signal; Transmembrane; Transmembrane helix; Zinc.
FT   SIGNAL        1     33       {ECO:0000269|PubMed:1654880,
FT                                ECO:0000269|PubMed:6291514,
FT                                ECO:0000269|PubMed:6314908}.
FT   CHAIN        34   1310       Angiotensin-converting enzyme.
FT                                /FTId=PRO_0000028551.
FT   CHAIN        34   1236       Angiotensin-converting enzyme, soluble
FT                                form.
FT                                /FTId=PRO_0000028552.
FT   PROPEP     1237   1310       Removed in secreted form. {ECO:0000250}.
FT                                /FTId=PRO_0000028553.
FT   TOPO_DOM     34   1260       Extracellular. {ECO:0000255}.
FT   TRANSMEM   1261   1281       Helical. {ECO:0000255}.
FT   TOPO_DOM   1282   1310       Cytoplasmic. {ECO:0000255}.
FT   REGION       35    634       Peptidase M2 1.
FT   REGION      635   1236       Peptidase M2 2.
FT   ACT_SITE    396    396       1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU10095}.
FT   ACT_SITE    993    993       2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU10095}.
FT   METAL       395    395       Zinc 1; catalytic. {ECO:0000250}.
FT   METAL       399    399       Zinc 1; catalytic. {ECO:0000250}.
FT   METAL       422    422       Zinc 1; catalytic. {ECO:0000250}.
FT   METAL       992    992       Zinc 2; catalytic. {ECO:0000250}.
FT   METAL       996    996       Zinc 2; catalytic. {ECO:0000250}.
FT   METAL      1020   1020       Zinc 2; catalytic. {ECO:0000250}.
FT   BINDING     236    236       Chloride 1. {ECO:0000250}.
FT   BINDING     533    533       Chloride 1. {ECO:0000250}.
FT   BINDING     795    795       Chloride 2. {ECO:0000250}.
FT   BINDING     833    833       Chloride 3. {ECO:0000250}.
FT   BINDING    1094   1094       Chloride 2. {ECO:0000250}.
FT   BINDING    1098   1098       Chloride 2. {ECO:0000250}.
FT   BINDING    1131   1131       Chloride 3. {ECO:0000250}.
FT   SITE       1237   1238       Cleavage.
FT   MOD_RES    1303   1303       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:P12821}.
FT   CARBOHYD     59     59       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD     79     79       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    151    151       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    323    323       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    449    449       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    513    513       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    681    681       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    699    699       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    718    718       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    946    946       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1195   1195       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID    162    170       {ECO:0000250}.
FT   DISULFID    761    767       {ECO:0000250}.
FT   DISULFID    961    979       {ECO:0000250}.
FT   DISULFID   1147   1159       {ECO:0000250}.
FT   VAR_SEQ       1    573       Missing (in isoform Testis-specific).
FT                                {ECO:0000303|PubMed:2550457}.
FT                                /FTId=VSP_037644.
FT   VAR_SEQ     574    645       RAVLQAGCSRPWQEVLKDMVASDALDAQPLLDYFQPVTQWL
FT                                QEQNERNGEVLGWPEYQWRPPLPNNYPEGID -> MGQGWA
FT                                APGLPSLLLLLLCCGHSLLVPSRVAARRVTVNQGTTSQATT
FT                                TSKATTSIRATTHQTTAHQTTQSPN (in isoform
FT                                Testis-specific).
FT                                {ECO:0000303|PubMed:2550457}.
FT                                /FTId=VSP_037645.
FT   MUTAGEN     727    727       K->E: No effect on activity. 20-fold
FT                                reduction in catalytic efficiency; when
FT                                associated with F-809.
FT                                {ECO:0000269|PubMed:7902354}.
FT   MUTAGEN     809    809       Y->F: No effect on activity. 20-fold
FT                                reduction in catalytic efficiency; when
FT                                associated with E-727.
FT                                {ECO:0000269|PubMed:7902354}.
FT   CONFLICT     48     48       E -> N (in Ref. 6; AA sequence).
FT                                {ECO:0000305}.
SQ   SEQUENCE   1310 AA;  150406 MW;  04777FAB17981DEA CRC64;
     MGAAPGRRGP RLLRPPPPLL LLLLLLRPPP AALTLDPGLL PGDFAADEAG ARLFASSYNS
     SAEQVLFRST AASWAHDTNI TAENARRQEE EALLSQEFAE AWGKKAKELY DPVWQNFTDP
     ELRRIIGAVR TLGPANLPLA KRQQYNSLLS NMSQIYSTGK VCFPNKTASC WSLDPDLNNI
     LASSRSYAML LFAWEGWHNA VGIPLKPLYQ EFTALSNEAY RQDGFSDTGA YWRSWYDSPT
     FEEDLERIYH QLEPLYLNLH AYVRRVLHRR YGDRYINLRG PIPAHLLGNM WAQSWESIYD
     MVVPFPDKPN LDVTSTMVQK GWNATHMFRV AEEFFTSLGL LPMPPEFWAE SMLEKPEDGR
     EVVCHASAWD FYNRKDFRIK QCTQVTMDQL STVHHEMGHV QYYLQYKDQP VSLRRANPGF
     HEAIGDVLAL SVSTPAHLHK IGLLDHVTND TESDINYLLK MALEKIAFLP FGYLVDQWRW
     GVFSGRTPSS RYNFDWWYLR TKYQGICPPV VRNETHFDAG AKFHIPSVTP YIRYFVSFVL
     QFQFHQALCM EAGHQGPLHQ CDIYQSTRAG AKLRAVLQAG CSRPWQEVLK DMVASDALDA
     QPLLDYFQPV TQWLQEQNER NGEVLGWPEY QWRPPLPNNY PEGIDLVTDE AEASRFVEEY
     DRSFQAVWNE YAEANWNYNT NITTEASKIL LQKNMQIANH TLTYGNWARR FDVSNFQNAT
     SKRIIKKVQD LQRAVLPVKE LEEYNQILLD METIYSVANV CRVDGSCLQL EPDLTNLMAT
     SRKYDELLWV WTSWRDKVGR AILPYFPKYV EFTNKAARLN GYVDAGDSWR SMYETPTLEQ
     DLERLFQELQ PLYLNLHAYV GRALHRHYGA QHINLEGPIP AHLLGNMWAQ TWSNIYDLVA
     PFPSASTMDA TEAMIKQGWT PRRMFEEADK FFISLGLLPV PPEFWNKSML EKPTDGREVV
     CHASAWDFYN GKDFRIKQCT TVNMEDLVVV HHEMGHIQYF MQYKDLPVAL REGANPGFHE
     AIGDVLALSV STPKHLHSIN LLSSEGGGYE HDINFLMKMA LDKIAFIPFS YLVDEWRWRV
     FDGSITKENY NQEWWSLRLK YQGLCPPAPR SQGDFDPGAK FHIPSSVPYI RYFVSFIIQF
     QFHEALCKAA GHTGPLHTCD IYQSKEAGKR LADAMKLGYS KPWPEAMKVI TGQPNMSASA
     MMNYFKPLMD WLLTENGRHG EKLGWPQYTW TPNSARSEGS LPDSGRVNFL GMNLDAQQAR
     VGQWVLLFLG VALLLASLGL TQRLFSIRYQ SLRQPHHGPQ FGSEVELRHS
//
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