ID   PENK_BOVIN              Reviewed;         263 AA.
AC   P01211; Q2T9T4;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   04-NOV-2026, entry version 144.
DE   RecName: Full=Proenkephalin-A;
DE   Contains:
DE     RecName: Full=Synenkephalin;
DE   Contains:
DE     RecName: Full=Met-enkephalin {ECO:0000303|PubMed:12869695};
DE     AltName: Full=Opioid growth factor;
DE              Short=OGF;
DE   Contains:
DE     RecName: Full=PENK(111-130) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=PENK(140-179) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=Met-enkephalin-Arg-Gly-Leu;
DE   Contains:
DE     RecName: Full=Leu-enkephalin;
DE   Contains:
DE     RecName: Full=Enkelytin {ECO:0000303|PubMed:8654396};
DE   Contains:
DE     RecName: Full=PENK(233-254) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=Met-enkephalin-Arg-Phe;
DE   Contains:
DE     RecName: Full=Neuropeptide BAM22;
DE     AltName: Full=Bovine adrenal medulla peptide 22;
DE              Short=BAM-22P {ECO:0000303|PubMed:7213356};
DE   Contains:
DE     RecName: Full=Neuropeptide BAM20;
DE     AltName: Full=Bovine adrenal medulla peptide 20;
DE              Short=BAM-20P {ECO:0000303|PubMed:7213356};
DE   Contains:
DE     RecName: Full=Neuropeptide BAM8-22;
DE     AltName: Full=Bovine adrenal medulla peptide 8-22;
DE              Short=BAM(8-22);
DE   Flags: Precursor;
GN   Name=PENK;
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=6276759; DOI=10.1038/295202a0;
RA   Noda M., Furutani Y., Takahashi H., Toyosato M., Hirose T., Inayama S.,
RA   Nakanishi S., Numa S.;
RT   "Cloning and sequence analysis of cDNA for bovine adrenal
RT   preproenkephalin.";
RL   Nature 295:202-206(1982).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Crossbred X Angus; TISSUE=Liver;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 47-263.
RX   PubMed=6173760; DOI=10.1038/295206a0;
RA   Gubler U., Seeburg P., Hoffman B.J., Gage L.P., Udenfriend S.;
RT   "Molecular cloning establishes proenkephalin as precursor of enkephalin-
RT   containing peptides.";
RL   Nature 295:206-208(1982).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 211-229.
RX   PubMed=6952189; DOI=10.1073/pnas.79.2.360;
RA   Comb M., Herbert E., Crea R.;
RT   "Partial characterization of the mRNA that codes for enkephalins in bovine
RT   adrenal medulla and human pheochromocytoma.";
RL   Proc. Natl. Acad. Sci. U.S.A. 79:360-364(1982).
RN   [5]
RP   PROTEIN SEQUENCE OF 233-261, AND FUNCTION.
RC   TISSUE=Chromaffin cell;
RX   PubMed=8654396; DOI=10.1111/j.1432-1033.1996.t01-1-00516.x;
RA   Goumon Y., Strub J.-M., Moniatte M., Nulans G., Poteur L., Hubert P.,
RA   van Dorsselaer A., Aunis D., Metz-Boutigue M.-H.;
RT   "The C-terminal bisphosphorylated proenkephalin-A-(209-237)-peptide from
RT   adrenal medullary chromaffin granules possesses antibacterial activity.";
RL   Eur. J. Biochem. 235:516-525(1996).
RN   [6]
RP   PROTEIN SEQUENCE OF 206-227, AND FUNCTION (NEUROPEPTIDE BAM22).
RX   PubMed=7213356; DOI=10.1016/s0006-291x(80)80005-2;
RA   Mizuno K., Minamino N., Kangawa K., Matsuo H.;
RT   "A new family of endogenous 'big' Met-enkephalins from bovine adrenal
RT   medulla: purification and structure of docosa- (BAM-22P) and eicosapeptide
RT   (BAM-20P) with very potent opiate activity.";
RL   Biochem. Biophys. Res. Commun. 97:1283-1290(1980).
RN   [7]
RP   PROTEOLYTIC CLEAVAGE, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX   PubMed=12869695; DOI=10.1073/pnas.1531542100;
RA   Yasothornsrikul S., Greenbaum D., Medzihradszky K.F., Toneff T., Bundey R.,
RA   Miller R., Schilling B., Petermann I., Dehnert J., Logvinova A.,
RA   Goldsmith P., Neveu J.M., Lane W.S., Gibson B., Reinheckel T., Peters C.,
RA   Bogyo M., Hook V.;
RT   "Cathepsin L in secretory vesicles functions as a prohormone-processing
RT   enzyme for production of the enkephalin peptide neurotransmitter.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:9590-9595(2003).
RN   [8]
RP   FUNCTION.
RX   PubMed=30243794; DOI=10.1016/j.toxicon.2018.09.002;
RA   Espino S.S., Robinson S.D., Safavi-Hemami H., Gajewiak J., Yang W.,
RA   Olivera B.M., Liu Q.;
RT   "Conopeptides promote itch through human itch receptor hMgprX1.";
RL   Toxicon 154:28-34(2018).
CC   -!- FUNCTION: [Met-enkephalin]: Neuropeptide that competes with and mimic
CC       the effects of opiate drugs. They play a role in a number of
CC       physiologic functions, including pain perception and responses to
CC       stress. {ECO:0000250|UniProtKB:P01210}.
CC   -!- FUNCTION: [Leu-enkephalin]: Neuropeptide that competes with and mimic
CC       the effects of opiate drugs. They play a role in a number of
CC       physiologic functions, including pain perception and responses to
CC       stress. {ECO:0000250|UniProtKB:P01210}.
CC   -!- FUNCTION: [Met-enkephalin-Arg-Phe]: Met-enkephalin-Arg-Phe neuropeptide
CC       acts as a strong ligand of Mu-type opioid receptor OPRM1. Met-
CC       enkephalin-Arg-Phe-binding to OPRM1 in the nucleus accumbens of the
CC       brain increases activation of OPRM1, leading to long-term synaptic
CC       depression of glutamate release. {ECO:0000250|UniProtKB:P22005}.
CC   -!- FUNCTION: [PENK(111-130)]: Increases glutamate release in the striatum
CC       and decreases GABA concentration in the striatum.
CC       {ECO:0000250|UniProtKB:P04094}.
CC   -!- FUNCTION: [PENK(233-254)]: Increases glutamate release in the striatum.
CC       {ECO:0000250|UniProtKB:P04094}.
CC   -!- FUNCTION: [Enkelytin]: Enkelytin possesses antibacterial activity
CC       against Gram-positive bacteria such as Micrococcus luteus and Bacillus
CC       megaterium. {ECO:0000269|PubMed:8654396}.
CC   -!- FUNCTION: [Neuropeptide BAM22]: Neuropeptide that mediates stress-
CC       induced opioid analgesia (Probable). Also possesses non-opioid action
CC       by acting as a ligand for MRGPRX1 receptor to induce itch in a
CC       histamine-independent manner (By similarity).
CC       {ECO:0000250|UniProtKB:P01210, ECO:0000305|PubMed:7213356}.
CC   -!- FUNCTION: [Neuropeptide BAM8-22]: Neuropeptide that induces itch in a
CC       histamine-independent manner as well as nociceptive sensations (By
CC       similarity). Acts as a ligand for MRGPRX1 receptor in sensory neurons
CC       of dorsal root ganglion: MRGPRX1-binding in the peripheral nervous
CC       system elicits itch and scratching, while MRGPRX1-binding in the
CC       central nervous system dampens chronic pain (By similarity).
CC       {ECO:0000250|UniProtKB:P01210}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle,
CC       chromaffin granule lumen {ECO:0000269|PubMed:12869695}. Secreted
CC       {ECO:0000305|PubMed:12869695}.
CC   -!- TISSUE SPECIFICITY: Secreted by neuroendocrine chromaffin cells through
CC       cromaffin granules. {ECO:0000269|PubMed:12869695}.
CC   -!- PTM: Proenkephalin-A is cleaved by CTSL to generate Met-enkephalin.
CC       {ECO:0000269|PubMed:12869695}.
CC   -!- PTM: [Met-enkephalin]: Processed and degraded by ACE.
CC       {ECO:0000250|UniProtKB:P01210}.
CC   -!- PTM: [Leu-enkephalin]: Processed and degraded by ACE.
CC       {ECO:0000250|UniProtKB:P01210}.
CC   -!- PTM: [Met-enkephalin-Arg-Gly-Leu]: Probably cleaved by ACE.
CC       {ECO:0000250|UniProtKB:P01210}.
CC   -!- PTM: [Met-enkephalin-Arg-Phe]: Processed by ACE to generate Met-
CC       enkephalin in the nucleus accumbens of the brain.
CC       {ECO:0000250|UniProtKB:P04094}.
CC   -!- PTM: The N-terminal domain contains 6 conserved cysteines thought to be
CC       involved in disulfide bonding and/or processing.
CC       {ECO:0000250|UniProtKB:P01210}.
CC   -!- SIMILARITY: Belongs to the opioid neuropeptide precursor family.
CC       {ECO:0000305}.
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DR   EMBL; V00109; CAA23443.1; -; mRNA.
DR   EMBL; BC111279; AAI11280.1; -; mRNA.
DR   EMBL; V00108; CAA23442.1; -; mRNA.
DR   EMBL; J00012; AAA30673.1; -; mRNA.
DR   PIR; A93272; EQBOA.
DR   RefSeq; NP_776566.1; NM_174141.2.
DR   AlphaFoldDB; P01211; -.
DR   EMDB; EMD-27752; -.
DR   EMDB; EMD-27753; -.
DR   FunCoup; P01211; 367.
DR   STRING; 9913.ENSBTAP00000066399; -.
DR   iPTMnet; P01211; -.
DR   PaxDb; 9913-ENSBTAP00000066399; -.
DR   Ensembl; ENSBTAT00000006478.5; ENSBTAP00000006478.3; ENSBTAG00000004924.5.
DR   Ensembl; ENSBTAT00085082836; ENSBTAP00085011963; ENSBTAG00085018967.
DR   Ensembl; ENSBTAT00090028862; ENSBTAP00090014987; ENSBTAG00090014488.
DR   GeneID; 281387; -.
DR   KEGG; bta:281387; -.
DR   CTD; 5179; -.
DR   VEuPathDB; HostDB:ENSBTAG00000004924; -.
DR   VGNC; VGNC:32746; PENK.
DR   eggNOG; ENOG502QWWK; Eukaryota.
DR   GeneTree; ENSGT00950000183149; -.
DR   HOGENOM; CLU_070973_0_0_1; -.
DR   InParanoid; P01211; -.
DR   OMA; ACIMECE; -.
DR   OrthoDB; 9928775at2759; -.
DR   Reactome; R-BTA-375276; Peptide ligand-binding receptors.
DR   Reactome; R-BTA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   Reactome; R-BTA-418594; G alpha (i) signalling events.
DR   Reactome; R-BTA-8957275; Post-translational protein phosphorylation.
DR   PRO; PR:P01211; -.
DR   Proteomes; UP000009136; Chromosome 14.
DR   Bgee; ENSBTAG00000004924; Expressed in urethra and 88 other cell types or tissues.
DR   GO; GO:0034466; C:chromaffin granule lumen; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0043025; C:neuronal cell body; IBA:GO_Central.
DR   GO; GO:0099013; C:neuronal dense core vesicle lumen; IBA:GO_Central.
DR   GO; GO:0001515; F:opioid peptide activity; IBA:GO_Central.
DR   GO; GO:0031628; F:opioid receptor binding; IBA:GO_Central.
DR   GO; GO:0007218; P:neuropeptide signaling pathway; IBA:GO_Central.
DR   GO; GO:0160025; P:sensory perception of itch; IEA:Ensembl.
DR   GO; GO:0019233; P:sensory perception of pain; IBA:GO_Central.
DR   InterPro; IPR006024; Opioid_neupept.
DR   InterPro; IPR000703; Proenkphlin_A.
DR   PANTHER; PTHR11438; PROENKEPHALIN; 1.
DR   PANTHER; PTHR11438:SF3; PROENKEPHALIN-A; 1.
DR   Pfam; PF01160; Opiods_neuropep; 1.
DR   PRINTS; PR01028; OPIOIDPRCRSR.
DR   PRINTS; PR01029; PENKAPRCRSR.
DR   PROSITE; PS01252; OPIOIDS_PRECURSOR; 1.
PE   1: Evidence at protein level;
KW   Antibiotic; Antimicrobial; Cleavage on pair of basic residues;
KW   Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond; Endorphin;
KW   Neuropeptide; Opioid peptide; Phosphoprotein; Reference proteome; Secreted;
KW   Signal.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000255"
FT   PEPTIDE         25..94
FT                   /note="Synenkephalin"
FT                   /id="PRO_0000008206"
FT   PEPTIDE         97..101
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008207"
FT   PEPTIDE         104..108
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008208"
FT   PEPTIDE         111..130
FT                   /note="PENK(111-130)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377682"
FT   PEPTIDE         133..137
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008210"
FT   PEPTIDE         140..179
FT                   /note="PENK(140-179)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377683"
FT   PEPTIDE         182..189
FT                   /note="Met-enkephalin-Arg-Gly-Leu"
FT                   /id="PRO_0000008212"
FT   PROPEP          192..203
FT                   /id="PRO_0000008213"
FT   PEPTIDE         206..227
FT                   /note="Neuropeptide BAM22"
FT                   /evidence="ECO:0000269|PubMed:7213356"
FT                   /id="PRO_0000462965"
FT   PEPTIDE         206..225
FT                   /note="Neuropeptide BAM20"
FT                   /evidence="ECO:0000269|PubMed:7213356"
FT                   /id="PRO_0000462966"
FT   PEPTIDE         206..210
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008214"
FT   PEPTIDE         213..227
FT                   /note="Neuropeptide BAM8-22"
FT                   /evidence="ECO:0000250|UniProtKB:P01210"
FT                   /id="PRO_0000462967"
FT   PEPTIDE         226..230
FT                   /note="Leu-enkephalin"
FT                   /id="PRO_0000008216"
FT   PEPTIDE         233..261
FT                   /note="Enkelytin"
FT                   /evidence="ECO:0000269|PubMed:8654396"
FT                   /id="PRO_0000008217"
FT   PEPTIDE         233..254
FT                   /note="PENK(233-254)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377684"
FT   PEPTIDE         257..263
FT                   /note="Met-enkephalin-Arg-Phe"
FT                   /id="PRO_0000008218"
FT   SITE            108..109
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   SITE            109..110
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   SITE            130..131
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   SITE            210..211
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   SITE            211..212
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   SITE            214..215
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000269|PubMed:12869695"
FT   MOD_RES         247
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT   DISULFID        26..48
FT                   /evidence="ECO:0000250|UniProtKB:P01210"
FT   DISULFID        30..52
FT                   /evidence="ECO:0000250|UniProtKB:P01210"
FT   DISULFID        33..65
FT                   /evidence="ECO:0000250|UniProtKB:P01210"
SQ   SEQUENCE   263 AA;  29788 MW;  0E400338A228B0D8 CRC64;
     MARFLGLCTW LLALGPGLLA TVRAECSQDC ATCSYRLARP TDLNPLACTL ECEGKLPSLK
     TWETCKELLQ LTKLELPPDA TSALSKQEES HLLAKKYGGF MKRYGGFMKK MDELYPLEVE
     EEANGGEVLG KRYGGFMKKD AEEDDGLGNS SNLLKELLGA GDQREGSLHQ EGSDAEDVSK
     RYGGFMRGLK RSPHLEDETK ELQKRYGGFM RRVGRPEWWM DYQKRYGGFL KRFAEPLPSE
     EEGESYSKEV PEMEKRYGGF MRF
//