ID   PENK_HUMAN              Reviewed;         267 AA.
AC   P01210; B2RC23; Q6FHC6; Q6FHE6;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   02-SEP-2026, entry version 203.
DE   RecName: Full=Proenkephalin-A {ECO:0000305};
DE   Contains:
DE     RecName: Full=Synenkephalin {ECO:0000303|PubMed:9126357};
DE   Contains:
DE     RecName: Full=Met-enkephalin {ECO:0000303|PubMed:656131};
DE     AltName: Full=Opioid growth factor;
DE              Short=OGF;
DE   Contains:
DE     RecName: Full=PENK(114-133) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=PENK(143-183) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=Met-enkephalin-Arg-Gly-Leu {ECO:0000303|PubMed:2982830};
DE   Contains:
DE     RecName: Full=Leu-enkephalin {ECO:0000303|PubMed:656131};
DE   Contains:
DE     RecName: Full=PENK(237-258) {ECO:0000250|UniProtKB:P04094};
DE   Contains:
DE     RecName: Full=Met-enkephalin-Arg-Phe {ECO:0000250|UniProtKB:P22005};
DE   Contains:
DE     RecName: Full=Neuropeptide BAM22 {ECO:0000303|PubMed:11850634};
DE     AltName: Full=Bovine adrenal medulla peptide 22;
DE   Contains:
DE     RecName: Full=Neuropeptide BAM20 {ECO:0000303|PubMed:11850634};
DE     AltName: Full=Bovine adrenal medulla peptide 20;
DE   Contains:
DE     RecName: Full=Neuropeptide BAM8-22 {ECO:0000303|PubMed:11850634};
DE     AltName: Full=Bovine adrenal medulla peptide 8-22;
DE              Short=BAM(8-22) {ECO:0000303|PubMed:11850634};
DE   Flags: Precursor;
GN   Name=PENK {ECO:0000312|HGNC:HGNC:8831};
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], AND FUNCTION.
RX   PubMed=7057924; DOI=10.1038/295663a0;
RA   Comb M., Seeburg P.H., Adelman J., Eiden L., Herbert E.;
RT   "Primary structure of the human Met- and Leu-enkephalin precursor and its
RT   mRNA.";
RL   Nature 295:663-666(1982).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=6281660; DOI=10.1038/297431a0;
RA   Noda M., Teranishi Y., Takahashi H., Toyosato M., Notake M., Nakanishi S.,
RA   Numa S.;
RT   "Isolation and structural organization of the human preproenkephalin
RT   gene.";
RL   Nature 297:431-434(1982).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Cerebellum;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA   Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA   LaBaer J.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.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   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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   [7]
RP   PROTEOLYTIC CLEAVAGE (MET-ENKEPHALIN AND LEU-ENKEPHALIN).
RX   PubMed=656131; DOI=10.1016/0006-2952(78)90542-7;
RA   Erdoes E.G., Johnson A.R., Boyden N.T.;
RT   "Hydrolysis of enkephalin by cultured human endothelial cells and by
RT   purified peptidyl dipeptidase.";
RL   Biochem. Pharmacol. 27:843-848(1978).
RN   [8]
RP   PROTEOLYTIC CLEAVAGE (MET-ENKEPHALIN-ARG-GLY-LEU).
RX   PubMed=2982830; DOI=10.1016/s0021-9258(18)89410-8;
RA   Norman J.A., Chang J.Y.;
RT   "Proteolytic conversion of [Met]enkephalin-Arg6-Gly7-Leu8 by brain synaptic
RT   membranes. Characterization of formed peptides and mechanism of
RT   proteolysis.";
RL   J. Biol. Chem. 260:2653-2656(1985).
RN   [9]
RP   DISULFIDE BONDS.
RX   PubMed=9126357; DOI=10.1006/bbrc.1997.6373;
RA   Lecchi P., Loh Y.P., Snell C.R., Pannell L.K.;
RT   "The structure of synenkephalin (pro-enkephalin 1-73) is dictated by three
RT   disulfide bonds.";
RL   Biochem. Biophys. Res. Commun. 232:800-805(1997).
RN   [10]
RP   FUNCTION (NEUROPEPTIDE BAM22 AND NEUROPEPTIDE BAM8-22).
RX   PubMed=11850634; DOI=10.1038/nn815;
RA   Lembo P.M.C., Grazzini E., Groblewski T., O'Donnell D., Roy M.-O.,
RA   Zhang J., Hoffert C., Cao J., Schmidt R., Pelletier M., Labarre M.,
RA   Gosselin M., Fortin Y., Banville D., Shen S., Stroem P., Payza K., Dray A.,
RA   Walker P., Ahmad S.;
RT   "Proenkephalin A gene products activate a new family of sensory neuron-
RT   specific GPCRs.";
RL   Nat. Neurosci. 5:201-209(2002).
RN   [11]
RP   FUNCTION (NEUROPEPTIDE BAM8-22).
RX   PubMed=21593341; DOI=10.1523/jneurosci.1192-11.2011;
RA   Sikand P., Dong X., LaMotte R.H.;
RT   "BAM8-22 peptide produces itch and nociceptive sensations in humans
RT   independent of histamine release.";
RL   J. Neurosci. 31:7563-7567(2011).
RN   [12]
RP   FUNCTION (NEUROPEPTIDE BAM8-22).
RX   PubMed=28223516; DOI=10.1073/pnas.1615255114;
RA   Li Z., Tseng P.Y., Tiwari V., Xu Q., He S.Q., Wang Y., Zheng Q., Han L.,
RA   Wu Z., Blobaum A.L., Cui Y., Tiwari V., Sun S., Cheng Y.,
RA   Huang-Lionnet J.H., Geng Y., Xiao B., Peng J., Hopkins C., Raja S.N.,
RA   Guan Y., Dong X.;
RT   "Targeting human Mas-related G protein-coupled receptor X1 to inhibit
RT   persistent pain.";
RL   Proc. Natl. Acad. Sci. U.S.A. 114:E1996-E2005(2017).
RN   [13]
RP   FUNCTION (NEUROPEPTIDE BAM8-22).
RX   PubMed=39725036; DOI=10.1016/j.jbc.2024.108125;
RA   Shiraishi A., Wada A., Satake H.;
RT   "Evolutionary scenarios for the specific recognition of nonhomologous
RT   endogenous peptides by G protein-coupled receptor paralogs.";
RL   J. Biol. Chem. 301:108125-108125(2025).
RN   [14] {ECO:0007744|PDB:8DWC, ECO:0007744|PDB:8DWG}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.71 ANGSTROMS) OF 217-231 IN COMPLEX
RP   WITH MRGPRX1; GNB1 AND GNG2, AND FUNCTION (NEUROPEPTIDE BAM8-22).
RX   PubMed=36302898; DOI=10.1038/s41589-022-01173-6;
RA   Liu Y., Cao C., Huang X.P., Gumpper R.H., Rachman M.M., Shih S.L.,
RA   Krumm B.E., Zhang S., Shoichet B.K., Fay J.F., Roth B.L.;
RT   "Ligand recognition and allosteric modulation of the human MRGPRX1
RT   receptor.";
RL   Nat. Chem. Biol. 19:416-422(2023).
RN   [15] {ECO:0007744|PDB:8JGF, ECO:0007744|PDB:8JGG}
RP   STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF 217-231 IN COMPLEX
RP   WITH MRGPRX1; GNAI1; GNB1 AND GNG2LEX WITH MRGPRX1; GNB1 AND GNG2, AND
RP   MUTAGENESIS OF ARG-229 AND TYR-230.
RX   PubMed=37591889; DOI=10.1038/s41467-023-40705-z;
RA   Guo L., Zhang Y., Fang G., Tie L., Zhuang Y., Xue C., Liu Q., Zhang M.,
RA   Zhu K., You C., Xu P., Yuan Q., Zhang C., Liu L., Rong N., Peng S., Liu Y.,
RA   Wang C., Luo X., Lv Z., Kang D., Yu X., Zhang C., Jiang Y., Dong X.,
RA   Zhou J., Liu Z., Yang F., Eric Xu H., Sun J.P.;
RT   "Ligand recognition and G protein coupling of the human itch receptor
RT   MRGPRX1.";
RL   Nat. Commun. 14:5004-5004(2023).
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:0000269|PubMed:7057924}.
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:0000269|PubMed:7057924}.
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(114-133)]: Increases glutamate release in the striatum
CC       and decreases GABA concentration in the striatum.
CC       {ECO:0000250|UniProtKB:P04094}.
CC   -!- FUNCTION: [Neuropeptide BAM22]: Neuropeptide that mediates stress-
CC       induced opioid analgesia (By similarity). Also possesses non-opioid
CC       action by acting as a ligand for MRGPRX1 receptor to induce itch in a
CC       histamine-independent manner (PubMed:11850634).
CC       {ECO:0000250|UniProtKB:P04094, ECO:0000269|PubMed:11850634}.
CC   -!- FUNCTION: [Neuropeptide BAM8-22]: Neuropeptide that induces itch in a
CC       histamine-independent manner as well as nociceptive sensations
CC       (PubMed:11850634, PubMed:28223516). Acts as a ligand for MRGPRX1
CC       receptor in sensory neurons of dorsal root ganglion: MRGPRX1-binding in
CC       the peripheral nervous system elicits itch and scratching, while
CC       MRGPRX1-binding in the central nervous system dampens chronic pain
CC       (PubMed:11850634, PubMed:21593341, PubMed:28223516, PubMed:36302898,
CC       PubMed:37591889, PubMed:39725036). {ECO:0000269|PubMed:11850634,
CC       ECO:0000269|PubMed:21593341, ECO:0000269|PubMed:28223516,
CC       ECO:0000269|PubMed:36302898, ECO:0000269|PubMed:37591889,
CC       ECO:0000269|PubMed:39725036}.
CC   -!- FUNCTION: [PENK(237-258)]: Increases glutamate release in the striatum.
CC       {ECO:0000250|UniProtKB:P04094}.
CC   -!- INTERACTION:
CC       PRO_0000008243; P35372: OPRM1; NbExp=3; IntAct=EBI-6656055, EBI-2624570;
CC   -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle,
CC       chromaffin granule lumen {ECO:0000250|UniProtKB:P01211}. Secreted
CC       {ECO:0000250|UniProtKB:P01211}.
CC   -!- PTM: Proenkephalin-A is cleaved by CTSL to generate Met-enkephalin.
CC       {ECO:0000250|UniProtKB:P01211}.
CC   -!- PTM: [Met-enkephalin]: Processed and degraded by ACE.
CC       {ECO:0000269|PubMed:656131}.
CC   -!- PTM: [Leu-enkephalin]: Processed and degraded by ACE.
CC       {ECO:0000269|PubMed:656131}.
CC   -!- PTM: [Met-enkephalin-Arg-Gly-Leu]: Probably cleaved by ACE.
CC       {ECO:0000305|PubMed:2982830}.
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:0000269|PubMed:9126357}.
CC   -!- SIMILARITY: Belongs to the opioid neuropeptide precursor family.
CC       {ECO:0000305}.
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DR   EMBL; V00509; CAA23767.1; -; Genomic_DNA.
DR   EMBL; J00123; AAB59409.1; -; Genomic_DNA.
DR   EMBL; J00122; AAB59409.1; JOINED; Genomic_DNA.
DR   EMBL; AK314908; BAG37420.1; -; mRNA.
DR   EMBL; CR541808; CAG46607.1; -; mRNA.
DR   EMBL; CR541828; CAG46627.1; -; mRNA.
DR   EMBL; CH471068; EAW86785.1; -; Genomic_DNA.
DR   EMBL; BC032505; AAH32505.1; -; mRNA.
DR   CCDS; CCDS6168.1; -.
DR   PIR; A93278; EQHUA.
DR   RefSeq; NP_001129162.1; NM_001135690.3.
DR   PDB; 1PLW; NMR; -; A=261-265.
DR   PDB; 1PLX; NMR; -; A=261-265.
DR   PDB; 2LWC; NMR; -; A=261-265.
DR   PDB; 5E33; X-ray; 1.84 A; B=261-265.
DR   PDB; 5E3A; X-ray; 2.05 A; B=230-234.
DR   PDB; 8DWC; EM; 2.87 A; A=217-231.
DR   PDB; 8DWG; EM; 2.71 A; A=217-231.
DR   PDB; 8JGF; EM; 2.70 A; L=217-231.
DR   PDB; 8JGG; EM; 3.00 A; L=220-230.
DR   AlphaFoldDB; P01210; -.
DR   EMDB; EMD-36232; -.
DR   EMDB; EMD-36233; -.
DR   MDposit; P01210; -.
DR   MDRepo; P01210; -.
DR   SMR; P01210; -.
DR   BioGRID; 111205; 10.
DR   FunCoup; P01210; 377.
DR   IntAct; P01210; 11.
DR   NDEx; IQUERY-CP-PENK; 1 NDEx IQuery Curated Pathway.
DR   STRING; 9606.ENSP00000400894; -.
DR   TCDB; 1.C.89.1.2; the dynorphin channel-forming neuropeptide (dynorphin) family.
DR   iPTMnet; P01210; -.
DR   PhosphoSitePlus; P01210; -.
DR   BioMuta; PENK; -.
DR   DMDM; 129770; -.
DR   MassIVE; P01210; -.
DR   PaxDb; 9606-ENSP00000400894; -.
DR   PeptideAtlas; P01210; -.
DR   ProteomicsDB; 51344; -.
DR   Antibodypedia; 2211; 375 antibodies from 38 providers.
DR   DNASU; 5179; -.
DR   Ensembl; ENST00000314922.3; ENSP00000324248.3; ENSG00000181195.12.
DR   Ensembl; ENST00000451791.7; ENSP00000400894.2; ENSG00000181195.12.
DR   Ensembl; ENST00000961478.1; ENSP00000631537.1; ENSG00000181195.12.
DR   Ensembl; ENST00000961479.1; ENSP00000631538.1; ENSG00000181195.12.
DR   Ensembl; ENST00000961480.1; ENSP00000631539.1; ENSG00000181195.12.
DR   Ensembl; ENST00000961481.1; ENSP00000631540.1; ENSG00000181195.12.
DR   GeneID; 5179; -.
DR   KEGG; hsa:5179; -.
DR   MANE-Select; ENST00000451791.7; ENSP00000400894.2; NM_001135690.3; NP_001129162.1.
DR   UCSC; uc003xsz.3; human.
DR   AGR; HGNC:8831; -.
DR   ClinPGx; PA33176; -.
DR   CTD; 5179; -.
DR   DisGeNET; 5179; -.
DR   GeneCards; PENK; -.
DR   HGNC; HGNC:8831; PENK.
DR   HPA; ENSG00000181195; Group enriched (adrenal gland, brain).
DR   MIM; 131330; gene.
DR   OpenTargets; ENSG00000181195; -.
DR   VEuPathDB; HostDB:ENSG00000181195; -.
DR   eggNOG; ENOG502QWWK; Eukaryota.
DR   GeneTree; ENSGT00950000183149; -.
DR   HOGENOM; CLU_070973_0_0_1; -.
DR   InParanoid; P01210; -.
DR   OMA; NPEAGHY; -.
DR   OrthoDB; 9928775at2759; -.
DR   PAN-GO; P01210; 8 GO annotations based on evolutionary models.
DR   PhylomeDB; P01210; -.
DR   PathwayCommons; P01210; -.
DR   Reactome; R-HSA-375276; Peptide ligand-binding receptors.
DR   Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   Reactome; R-HSA-418594; G alpha (i) signalling events.
DR   Reactome; R-HSA-8957275; Post-translational protein phosphorylation.
DR   SignaLink; P01210; -.
DR   SIGNOR; P01210; -.
DR   Agora; ENSG00000181195; -.
DR   BioGRID-ORCS; 5179; 7 hits in 1140 CRISPR screens.
DR   ChiTaRS; PENK; human.
DR   EvolutionaryTrace; P01210; -.
DR   GenomeRNAi; 5179; -.
DR   Pharos; P01210; Tbio.
DR   PRO; PR:P01210; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; P01210; protein.
DR   Bgee; ENSG00000181195; Expressed in nucleus accumbens and 166 other cell types or tissues.
DR   ExpressionAtlas; P01210; baseline and differential.
DR   GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR   GO; GO:0070852; C:cell body fiber; IEA:Ensembl.
DR   GO; GO:0034466; C:chromaffin granule lumen; IEA:UniProtKB-SubCell.
DR   GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR   GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
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:0043204; C:perikaryon; IEA:Ensembl.
DR   GO; GO:0032280; C:symmetric synapse; IEA:Ensembl.
DR   GO; GO:0034592; C:synaptic vesicle lumen; IEA:Ensembl.
DR   GO; GO:0005184; F:neuropeptide hormone activity; TAS:ProtInc.
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:0048018; F:receptor ligand activity; IDA:UniProt.
DR   GO; GO:0048149; P:behavioral response to ethanol; IEA:Ensembl.
DR   GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR   GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
DR   GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEA:Ensembl.
DR   GO; GO:0098586; P:cellular response to virus; IEA:Ensembl.
DR   GO; GO:0071305; P:cellular response to vitamin D; IEA:Ensembl.
DR   GO; GO:0042756; P:drinking behavior; IEA:Ensembl.
DR   GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; IEA:Ensembl.
DR   GO; GO:0051867; P:general adaptation syndrome, behavioral process; IEA:Ensembl.
DR   GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl.
DR   GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl.
DR   GO; GO:0007218; P:neuropeptide signaling pathway; IBA:GO_Central.
DR   GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR   GO; GO:2000987; P:positive regulation of behavioral fear response; IEA:Ensembl.
DR   GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR   GO; GO:0071871; P:response to epinephrine; IEA:Ensembl.
DR   GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR   GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR   GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR   GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:0035094; P:response to nicotine; IEA:Ensembl.
DR   GO; GO:1901652; P:response to peptide; IEA:Ensembl.
DR   GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR   GO; GO:0160025; P:sensory perception of itch; IDA:UniProt.
DR   GO; GO:0019233; P:sensory perception of pain; IBA:GO_Central.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   GO; GO:0099538; P:synaptic signaling via neuropeptide; IEA:Ensembl.
DR   GO; GO:0019226; P:transmission of nerve impulse; IEA:Ensembl.
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.
DR   PDBsum; 1PLW; -.
DR   PDBsum; 1PLX; -.
DR   PDBsum; 2LWC; -.
DR   PDBsum; 5E33; -.
DR   PDBsum; 5E3A; -.
DR   PDBsum; 8DWC; -.
DR   PDBsum; 8DWG; -.
DR   PDBsum; 8JGF; -.
DR   PDBsum; 8JGG; -.
PE   1: Evidence at protein level;
KW   3D-structure; Cleavage on pair of basic residues; Cytoplasmic vesicle;
KW   Disulfide bond; Endorphin; Neuropeptide; Opioid peptide; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000255"
FT   PEPTIDE         25..97
FT                   /note="Synenkephalin"
FT                   /id="PRO_0000008242"
FT   PEPTIDE         100..104
FT                   /note="Met-enkephalin"
FT                   /evidence="ECO:0000269|PubMed:656131"
FT                   /id="PRO_0000008243"
FT   PEPTIDE         107..111
FT                   /note="Met-enkephalin"
FT                   /evidence="ECO:0000269|PubMed:656131"
FT                   /id="PRO_0000008244"
FT   PEPTIDE         114..133
FT                   /note="PENK(114-133)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377691"
FT   PEPTIDE         136..140
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008246"
FT   PEPTIDE         143..183
FT                   /note="PENK(143-183)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377692"
FT   PEPTIDE         186..193
FT                   /note="Met-enkephalin-Arg-Gly-Leu"
FT                   /evidence="ECO:0000269|PubMed:2982830"
FT                   /id="PRO_0000008248"
FT   PROPEP          196..207
FT                   /id="PRO_0000008249"
FT   PEPTIDE         210..231
FT                   /note="Neuropeptide BAM22"
FT                   /evidence="ECO:0000305|PubMed:11850634"
FT                   /id="PRO_0000462974"
FT   PEPTIDE         210..229
FT                   /note="Neuropeptide BAM20"
FT                   /evidence="ECO:0000305|PubMed:11850634"
FT                   /id="PRO_0000462975"
FT   PEPTIDE         210..214
FT                   /note="Met-enkephalin"
FT                   /id="PRO_0000008250"
FT   PEPTIDE         217..231
FT                   /note="Neuropeptide BAM8-22"
FT                   /evidence="ECO:0000305|PubMed:11850634"
FT                   /id="PRO_0000462976"
FT   PEPTIDE         230..234
FT                   /note="Leu-enkephalin"
FT                   /id="PRO_0000008252"
FT   PEPTIDE         237..258
FT                   /note="PENK(237-258)"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000377693"
FT   PEPTIDE         261..267
FT                   /note="Met-enkephalin-Arg-Phe"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT                   /id="PRO_0000008254"
FT   REGION          163..182
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        163..175
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            111..112
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   SITE            112..113
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   SITE            133..134
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   SITE            214..215
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   SITE            215..216
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   SITE            218..219
FT                   /note="Cleavage; by CTSL"
FT                   /evidence="ECO:0000250|UniProtKB:P01211"
FT   MOD_RES         251
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P04094"
FT   DISULFID        26..48
FT                   /evidence="ECO:0000269|PubMed:9126357"
FT   DISULFID        30..52
FT                   /evidence="ECO:0000269|PubMed:9126357"
FT   DISULFID        33..65
FT                   /evidence="ECO:0000269|PubMed:9126357"
FT   VARIANT         83
FT                   /note="T -> N (in dbSNP:rs11998459)"
FT                   /id="VAR_048935"
FT   VARIANT         247
FT                   /note="G -> D (in dbSNP:rs1800567)"
FT                   /id="VAR_014584"
FT   MUTAGEN         229
FT                   /note="R->A: Abolished ability to activate MRGPRX1."
FT                   /evidence="ECO:0000269|PubMed:37591889"
FT   MUTAGEN         230
FT                   /note="Y->A: Abolished ability to activate MRGPRX1."
FT                   /evidence="ECO:0000269|PubMed:37591889"
FT   CONFLICT        119
FT                   /note="P -> S (in Ref. 4; CAG46627)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        152
FT                   /note="N -> I (in Ref. 4; CAG46607)"
FT                   /evidence="ECO:0000305"
FT   TURN            225..227
FT                   /evidence="ECO:0007829|PDB:8JGF"
FT   TURN            262..264
FT                   /evidence="ECO:0007829|PDB:2LWC"
SQ   SEQUENCE   267 AA;  30787 MW;  4189BA600C3FC8EE CRC64;
     MARFLTLCTW LLLLGPGLLA TVRAECSQDC ATCSYRLVRP ADINFLACVM ECEGKLPSLK
     IWETCKELLQ LSKPELPQDG TSTLRENSKP EESHLLAKRY GGFMKRYGGF MKKMDELYPM
     EPEEEANGSE ILAKRYGGFM KKDAEEDDSL ANSSDLLKEL LETGDNRERS HHQDGSDNEE
     EVSKRYGGFM RGLKRSPQLE DEAKELQKRY GGFMRRVGRP EWWMDYQKRY GGFLKRFAEA
     LPSDEEGESY SKEVPEMEKR YGGFMRF
//