ID   PEPA5_HUMAN             Reviewed;         388 AA.
AC   P0DJD9; A8K749; B7ZW62; B7ZW75; P00790; Q7M4R0; Q8N1E3;
DT   22-FEB-2012, integrated into UniProtKB/Swiss-Prot.
DT   22-FEB-2012, sequence version 1.
DT   27-MAR-2024, entry version 85.
DE   RecName: Full=Pepsin A-5;
DE            EC=3.4.23.1;
DE   AltName: Full=Pepsinogen-5;
DE   Flags: Precursor;
GN   Name=PGA5;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   TISSUE=Placenta;
RX   PubMed=2714789; DOI=10.1016/0888-7543(89)90325-x;
RA   Evers M.P.J., Zelle B., Bebelman J.-P., van Beusechem V., Kraakman L.,
RA   Hoffer M.J.V., Pronk J.C., Mager W.H., Planta R.J., Eriksson A.W.,
RA   Frants R.R.;
RT   "Nucleotide sequence comparison of five human pepsinogen A (PGA) genes:
RT   evolution of the PGA multigene family.";
RL   Genomics 4:232-239(1989).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, Colon, Kidney, and Stomach;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   PARTIAL PROTEIN SEQUENCE OF 1-28.
RX   PubMed=2415509; DOI=10.1093/oxfordjournals.jbchem.a135303;
RA   Ichihara Y., Sogawa K., Takahashi K.;
RT   "Isolation of human, swine, and rat prepepsinogens and calf preprochymosin,
RT   and determination of the primary structures of their NH2-terminal signal
RT   sequences.";
RL   J. Biochem. 98:483-492(1985).
RN   [6]
RP   PROTEIN SEQUENCE OF 16-100.
RX   PubMed=2515193; DOI=10.1093/oxfordjournals.jbchem.a122952;
RA   Athauda S.B.P., Tanji M., Kageyama T., Takahashi K.;
RT   "A comparative study on the NH2-terminal amino acid sequences and some
RT   other properties of six isozymic forms of human pepsinogens and pepsins.";
RL   J. Biochem. 106:920-927(1989).
RN   [7]
RP   PROTEIN SEQUENCE OF 16-68.
RX   PubMed=3197840; DOI=10.1016/0014-5793(88)81033-0;
RA   Foltmann B.;
RT   "Activation of human pepsinogens.";
RL   FEBS Lett. 241:69-72(1988).
RN   [8]
RP   PROTEIN SEQUENCE OF 362-388.
RX   PubMed=4909888; DOI=10.1016/s0021-9258(18)63137-0;
RA   Huang W.-Y., Tang J.;
RT   "Carboxyl-terminal sequence of human gastricsin and pepsin.";
RL   J. Biol. Chem. 245:2189-2193(1970).
RN   [9]
RP   IDENTIFICATION.
RX   PubMed=6300126; DOI=10.1016/s0021-9258(18)32572-9;
RA   Sogawa K., Fujii-Kuriyama Y., Mizukami Y., Ichihara Y., Takahashi K.;
RT   "Primary structure of human pepsinogen gene.";
RL   J. Biol. Chem. 258:5306-5311(1983).
RN   [10]
RP   X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 63-388, ACTIVE SITES, AND
RP   DISULFIDE BONDS.
RX   PubMed=7663352; DOI=10.1002/pro.5560040516;
RA   Fujinaga M., Chernaia M.M., Tarasova N.I., Mosimann S.C., James M.N.G.;
RT   "Crystal structure of human pepsin and its complex with pepstatin.";
RL   Protein Sci. 4:960-972(1995).
CC   -!- FUNCTION: Shows particularly broad specificity; although bonds
CC       involving phenylalanine and leucine are preferred, many others are also
CC       cleaved to some extent.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Preferential cleavage: hydrophobic, preferably aromatic,
CC         residues in P1 and P1' positions. Cleaves 1-Phe-|-Val-2, 4-Gln-|-His-
CC         5, 13-Glu-|-Ala-14, 14-Ala-|-Leu-15, 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-
CC         17, 23-Gly-|-Phe-24, 24-Phe-|-Phe-25 and 25-Phe-|-Tyr-26 bonds in the
CC         B chain of insulin.; EC=3.4.23.1; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU10094};
CC   -!- SUBCELLULAR LOCATION: Secreted.
CC   -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR   EMBL; M26032; AAA60061.1; -; Genomic_DNA.
DR   EMBL; M26025; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26026; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26027; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26028; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26029; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26030; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; M26031; AAA60061.1; JOINED; Genomic_DNA.
DR   EMBL; AP003037; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471076; EAW73928.1; -; Genomic_DNA.
DR   EMBL; BC029055; AAH29055.1; -; mRNA.
DR   EMBL; BC146999; AAI47000.1; -; mRNA.
DR   EMBL; BC171889; AAI71889.1; -; mRNA.
DR   CCDS; CCDS8001.1; -.
DR   PIR; A00980; PEHU.
DR   PIR; A30142; A30142.
DR   PIR; A92058; A92058.
DR   PIR; B30142; B30142.
DR   RefSeq; NP_055039.1; NM_014224.4.
DR   AlphaFoldDB; P0DJD9; -.
DR   SMR; P0DJD9; -.
DR   BioGRID; 111243; 1.
DR   STRING; 9606.ENSP00000309542; -.
DR   BindingDB; P0DJD9; -.
DR   ChEMBL; CHEMBL3295; -.
DR   DrugBank; DB00364; Sucralfate.
DR   DrugCentral; P0DJD9; -.
DR   GuidetoPHARMACOLOGY; 2390; -.
DR   MEROPS; A01.070; -.
DR   MEROPS; A01.071; -.
DR   iPTMnet; P0DJD9; -.
DR   PhosphoSitePlus; P0DJD9; -.
DR   BioMuta; PGA5; -.
DR   DMDM; 378522017; -.
DR   jPOST; P0DJD9; -.
DR   MassIVE; P0DJD9; -.
DR   PaxDb; 9606-ENSP00000309542; -.
DR   PeptideAtlas; P0DJD9; -.
DR   Antibodypedia; 65697; 200 antibodies from 23 providers.
DR   DNASU; 5222; -.
DR   Ensembl; ENST00000312403.10; ENSP00000309542.6; ENSG00000256713.8.
DR   GeneID; 5222; -.
DR   KEGG; hsa:5222; -.
DR   MANE-Select; ENST00000312403.10; ENSP00000309542.6; NM_014224.5; NP_055039.1.
DR   UCSC; uc001nqz.4; human.
DR   AGR; HGNC:8887; -.
DR   CTD; 5222; -.
DR   DisGeNET; 5222; -.
DR   GeneCards; PGA5; -.
DR   HGNC; HGNC:8887; PGA5.
DR   HPA; ENSG00000256713; Tissue enriched (stomach).
DR   MIM; 169700; gene.
DR   MIM; 169730; gene.
DR   neXtProt; NX_P0DJD9; -.
DR   OpenTargets; ENSG00000256713; -.
DR   PharmGKB; PA33224; -.
DR   VEuPathDB; HostDB:ENSG00000256713; -.
DR   eggNOG; KOG1339; Eukaryota.
DR   GeneTree; ENSGT00940000155036; -.
DR   HOGENOM; CLU_013253_3_0_1; -.
DR   InParanoid; P0DJD9; -.
DR   OMA; SECHIYK; -.
DR   OrthoDB; 1120702at2759; -.
DR   PhylomeDB; P0DJD9; -.
DR   TreeFam; TF314990; -.
DR   PathwayCommons; P0DJD9; -.
DR   Reactome; R-HSA-5683826; Surfactant metabolism.
DR   BioGRID-ORCS; 5222; 6 hits in 272 CRISPR screens.
DR   ChiTaRS; PGA5; human.
DR   GeneWiki; PGA5; -.
DR   GenomeRNAi; 5222; -.
DR   Pharos; P0DJD9; Tclin.
DR   PRO; PR:P0DJD9; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; P0DJD9; Protein.
DR   Bgee; ENSG00000256713; Expressed in body of stomach and 92 other cell types or tissues.
DR   ExpressionAtlas; P0DJD9; baseline and differential.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0097486; C:multivesicular body lumen; TAS:Reactome.
DR   GO; GO:0004190; F:aspartic-type endopeptidase activity; IBA:GO_Central.
DR   GO; GO:0007586; P:digestion; IEA:UniProtKB-KW.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   CDD; cd05478; pepsin_A; 1.
DR   Gene3D; 6.10.140.60; -; 1.
DR   Gene3D; 2.40.70.10; Acid Proteases; 2.
DR   InterPro; IPR001461; Aspartic_peptidase_A1.
DR   InterPro; IPR001969; Aspartic_peptidase_AS.
DR   InterPro; IPR012848; Aspartic_peptidase_N.
DR   InterPro; IPR034162; Pepsin_A.
DR   InterPro; IPR033121; PEPTIDASE_A1.
DR   InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR   PANTHER; PTHR47966; BETA-SITE APP-CLEAVING ENZYME, ISOFORM A-RELATED; 1.
DR   PANTHER; PTHR47966:SF22; PEPSIN A-3-RELATED; 1.
DR   Pfam; PF07966; A1_Propeptide; 1.
DR   Pfam; PF00026; Asp; 1.
DR   PRINTS; PR00792; PEPSIN.
DR   SUPFAM; SSF50630; Acid proteases; 1.
DR   PROSITE; PS00141; ASP_PROTEASE; 2.
DR   PROSITE; PS51767; PEPTIDASE_A1; 1.
DR   Genevisible; P0DJD9; HS.
PE   1: Evidence at protein level;
KW   Aspartyl protease; Digestion; Direct protein sequencing; Disulfide bond;
KW   Hydrolase; Phosphoprotein; Protease; Reference proteome; Secreted; Signal;
KW   Zymogen.
FT   SIGNAL          1..15
FT                   /evidence="ECO:0000269|PubMed:2515193,
FT                   ECO:0000269|PubMed:3197840"
FT   PROPEP          16..62
FT                   /note="Activation peptide"
FT                   /id="PRO_0000415759"
FT   CHAIN           63..388
FT                   /note="Pepsin A-5"
FT                   /id="PRO_0000415760"
FT   DOMAIN          76..385
FT                   /note="Peptidase A1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT   ACT_SITE        94
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10094,
FT                   ECO:0000269|PubMed:7663352"
FT   ACT_SITE        277
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10094,
FT                   ECO:0000269|PubMed:7663352"
FT   MOD_RES         130
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P03954"
FT   DISULFID        107..112
FT                   /evidence="ECO:0000269|PubMed:7663352"
FT   DISULFID        268..272
FT                   /evidence="ECO:0000269|PubMed:7663352"
FT   DISULFID        311..344
FT                   /evidence="ECO:0000269|PubMed:7663352"
FT   CONFLICT        28
FT                   /note="L -> F (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        58
FT                   /note="E -> K (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        92
FT                   /note="V -> L (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        222
FT                   /note="K -> Q (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        265
FT                   /note="T -> A (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        353
FT                   /note="V -> L (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        371..372
FT                   /note="YF -> FY (in Ref. 8; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        376
FT                   /note="D -> E (in Ref. 1; AAA60061)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   388 AA;  41993 MW;  2C456A75DA96CDDA CRC64;
     MKWLLLLGLV ALSECIMYKV PLIRKKSLRR TLSERGLLKD FLKKHNLNPA RKYFPQWEAP
     TLVDEQPLEN YLDMEYFGTI GIGTPAQDFT VVFDTGSSNL WVPSVYCSSL ACTNHNRFNP
     EDSSTYQSTS ETVSITYGTG SMTGILGYDT VQVGGISDTN QIFGLSETEP GSFLYYAPFD
     GILGLAYPSI SSSGATPVFD NIWNQGLVSQ DLFSVYLSAD DKSGSVVIFG GIDSSYYTGS
     LNWVPVTVEG YWQITVDSIT MNGETIACAE GCQAIVDTGT SLLTGPTSPI ANIQSDIGAS
     ENSDGDMVVS CSAISSLPDI VFTINGVQYP VPPSAYILQS EGSCISGFQG MNVPTESGEL
     WILGDVFIRQ YFTVFDRANN QVGLAPVA
//