Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEJ6430)

DOT Name Proenkephalin-B (PDYN)
Synonyms Beta-neoendorphin-dynorphin; Preprodynorphin
Gene Name PDYN
Related Disease
Respiratory disease ( )
Adenocarcinoma ( )
Alcohol use disorder ( )
Alzheimer disease ( )
Cardiac arrest ( )
Cerebellar disorder ( )
Cholestasis ( )
Cocaine addiction ( )
Dementia ( )
Depression ( )
Drug dependence ( )
Epilepsy ( )
Heroin dependence ( )
Herpes simplex infection ( )
HIV infectious disease ( )
Hypotension ( )
Inflammatory bowel disease ( )
Major depressive disorder ( )
Mood disorder ( )
Movement disorder ( )
Nervous system disease ( )
Neuralgia ( )
Non-small-cell lung cancer ( )
Pheochromocytoma ( )
Respiratory failure ( )
Small-cell lung cancer ( )
Spinocerebellar ataxia ( )
Spinocerebellar ataxia type 1 ( )
Spinocerebellar ataxia type 23 ( )
Spinocerebellar ataxia type 6 ( )
Squamous cell carcinoma ( )
Substance abuse ( )
Substance dependence ( )
Temporal lobe epilepsy ( )
Narcolepsy ( )
Neuroblastoma ( )
Autosomal recessive juvenile Parkinson disease 2 ( )
Cerebellar ataxia ( )
Juvenile-onset Parkinson disease ( )
Mental disorder ( )
Parkinsonian disorder ( )
UniProt ID
PDYN_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
2N2F; 7Y1F; 8F7W
Pfam ID
PF01160
Sequence
MAWQGLVLAACLLMFPSTTADCLSRCSLCAVKTQDGPKPINPLICSLQCQAALLPSEEWE
RCQSFLSFFTPSTLGLNDKEDLGSKSVGEGPYSELAKLSGSFLKELEKSKFLPSISTKEN
TLSKSLEEKLRGLSDGFREGAESELMRDAQLNDGAMETGTLYLAEEDPKEQVKRYGGFLR
KYPKRSSEVAGEGDGDSMGHEDLYKRYGGFLRRIRPKLKWDNQKRYGGFLRRQFKVVTRS
QEDPNAYSGELFDA
Function
Leu-enkephalins compete with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress; Dynorphin peptides differentially regulate the kappa opioid receptor. Dynorphin A(1-13) has a typical opioid activity, it is 700 times more potent than Leu-enkephalin; Leumorphin has a typical opioid activity and may have anti-apoptotic effect.
KEGG Pathway
Neuroactive ligand-receptor interaction (hsa04080 )
Spinocerebellar ataxia (hsa05017 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Cocaine addiction (hsa05030 )
Amphetamine addiction (hsa05031 )
Alcoholism (hsa05034 )
Reactome Pathway
G-protein activation (R-HSA-202040 )
Peptide ligand-binding receptors (R-HSA-375276 )
G alpha (i) signalling events (R-HSA-418594 )
Opioid Signalling (R-HSA-111885 )

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Respiratory disease DISGGAGJ Definitive Biomarker [1]
Adenocarcinoma DIS3IHTY Strong Genetic Variation [2]
Alcohol use disorder DISMB65Y Strong Biomarker [3]
Alzheimer disease DISF8S70 Strong Biomarker [4]
Cardiac arrest DIS9DIA4 Strong Genetic Variation [5]
Cerebellar disorder DIS2O7WM Strong Biomarker [6]
Cholestasis DISDJJWE Strong Biomarker [7]
Cocaine addiction DISHTRXG Strong Biomarker [8]
Dementia DISXL1WY Strong Biomarker [9]
Depression DIS3XJ69 Strong Biomarker [10]
Drug dependence DIS9IXRC Strong Biomarker [11]
Epilepsy DISBB28L Strong Altered Expression [12]
Heroin dependence DISQ1H57 Strong Genetic Variation [13]
Herpes simplex infection DISL1SAV Strong Genetic Variation [14]
HIV infectious disease DISO97HC Strong Genetic Variation [15]
Hypotension DISYNSM9 Strong Biomarker [16]
Inflammatory bowel disease DISGN23E Strong Biomarker [17]
Major depressive disorder DIS4CL3X Strong Biomarker [18]
Mood disorder DISLVMWO Strong Biomarker [19]
Movement disorder DISOJJ2D Strong Biomarker [20]
Nervous system disease DISJ7GGT Strong Biomarker [6]
Neuralgia DISWO58J Strong Biomarker [21]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [2]
Pheochromocytoma DIS56IFV Strong Biomarker [22]
Respiratory failure DISVMYJO Strong Therapeutic [23]
Small-cell lung cancer DISK3LZD Strong Altered Expression [24]
Spinocerebellar ataxia DISYMHUK Strong Genetic Variation [9]
Spinocerebellar ataxia type 1 DISF7BO2 Strong Genetic Variation [25]
Spinocerebellar ataxia type 23 DISAXT72 Strong Autosomal dominant [26]
Spinocerebellar ataxia type 6 DISH7224 Strong Genetic Variation [27]
Squamous cell carcinoma DISQVIFL Strong Biomarker [28]
Substance abuse DIS327VW Strong Biomarker [29]
Substance dependence DISDRAAR Strong Biomarker [10]
Temporal lobe epilepsy DISNOPXX Strong Biomarker [30]
Narcolepsy DISLCNLI moderate Genetic Variation [31]
Neuroblastoma DISVZBI4 moderate Altered Expression [32]
Autosomal recessive juvenile Parkinson disease 2 DISNSTD1 Limited Biomarker [33]
Cerebellar ataxia DIS9IRAV Limited Genetic Variation [5]
Juvenile-onset Parkinson disease DISNT5BI Limited Biomarker [33]
Mental disorder DIS3J5R8 Limited Genetic Variation [34]
Parkinsonian disorder DISHGY45 Limited Biomarker [33]
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⏷ Show the Full List of 41 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Methamphetamine DMPM4SK Approved Proenkephalin-B (PDYN) increases the response to substance of Methamphetamine. [29]
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16 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Proenkephalin-B (PDYN). [35]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Proenkephalin-B (PDYN). [36]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Proenkephalin-B (PDYN). [37]
Cisplatin DMRHGI9 Approved Cisplatin affects the expression of Proenkephalin-B (PDYN). [38]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Proenkephalin-B (PDYN). [39]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of Proenkephalin-B (PDYN). [40]
Decitabine DMQL8XJ Approved Decitabine affects the expression of Proenkephalin-B (PDYN). [38]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Proenkephalin-B (PDYN). [40]
Ethanol DMDRQZU Approved Ethanol decreases the expression of Proenkephalin-B (PDYN). [41]
Cocaine DMSOX7I Approved Cocaine increases the expression of Proenkephalin-B (PDYN). [42]
Heroin diacetylmorphine DMDBWHY Approved Heroin diacetylmorphine decreases the expression of Proenkephalin-B (PDYN). [43]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Proenkephalin-B (PDYN). [40]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of Proenkephalin-B (PDYN). [44]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Proenkephalin-B (PDYN). [45]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Proenkephalin-B (PDYN). [46]
4-hydroxy-2-nonenal DM2LJFZ Investigative 4-hydroxy-2-nonenal decreases the expression of Proenkephalin-B (PDYN). [39]
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⏷ Show the Full List of 16 Drug(s)

References

1 Differential cardiovascular effects of mu, delta and kappa opiate agonists at discrete hypothalamic sites in the anesthetized rat.Life Sci. 1982 Nov 15-22;31(20-21):2197-200. doi: 10.1016/0024-3205(82)90117-5.
2 SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens.Ann Diagn Pathol. 2017 Feb;26:47-51. doi: 10.1016/j.anndiagpath.2016.10.006. Epub 2016 Oct 20.
3 A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain.Neuropsychopharmacology. 2009 Apr;34(5):1185-97. doi: 10.1038/npp.2008.187. Epub 2008 Oct 15.
4 Dysregulation of dynorphins in Alzheimer disease.Neurobiol Aging. 2007 Nov;28(11):1700-8. doi: 10.1016/j.neurobiolaging.2006.07.002. Epub 2006 Aug 17.
5 Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases.J Neurol. 2013 Jul;260(7):1807-12. doi: 10.1007/s00415-013-6882-6. Epub 2013 Mar 8.
6 Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3.Am J Hum Genet. 1999 Aug;65(2):420-6. doi: 10.1086/302495.
7 Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats.Pharmacol Biochem Behav. 2006 Sep;85(1):39-43. doi: 10.1016/j.pbb.2006.07.004. Epub 2006 Aug 17.
8 Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.PLoS One. 2014 May 9;9(5):e97216. doi: 10.1371/journal.pone.0097216. eCollection 2014.
9 Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) associated with progressive cognitive and behavioral deterioration.Neuropsychology. 2017 Mar;31(3):292-303. doi: 10.1037/neu0000322. Epub 2016 Nov 21.
10 Neuronal Expression of Opioid Gene is Controlled by Dual Epigenetic and Transcriptional Mechanism in Human Brain.Cereb Cortex. 2018 Sep 1;28(9):3129-3142. doi: 10.1093/cercor/bhx181.
11 An analysis of genetic association in opioid dependence susceptibility.J Clin Pharm Ther. 2018 Feb;43(1):80-86. doi: 10.1111/jcpt.12585. Epub 2017 Jun 27.
12 Dynamic up-regulation of prodynorphin transcription in temporal lobe epilepsy.Hippocampus. 2009 Nov;19(11):1051-4. doi: 10.1002/hipo.20633.
13 Genetic association analyses and meta-analysis of Dynorphin-Kappa Opioid system potential functional variants with heroin dependence.Neurosci Lett. 2018 Oct 15;685:75-82. doi: 10.1016/j.neulet.2018.08.023. Epub 2018 Aug 20.
14 Gene therapy for the treatment of chronic peripheral nervous system pain.Neurobiol Dis. 2012 Nov;48(2):255-70. doi: 10.1016/j.nbd.2012.05.005. Epub 2012 Jun 2.
15 Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history.J Acquir Immune Defic Syndr. 2013 May 1;63(1):17-26. doi: 10.1097/QAI.0b013e318285cd0c.
16 Effects of dynorphin A(1-13) and of fragments of beta-endorphin on blood pressure and heart rate of anesthetized rats.Can J Physiol Pharmacol. 1991 Mar;69(3):327-33. doi: 10.1139/y91-050.
17 Enkephalin degradation in serum of patients with inflammatory bowel diseases.Pharmacol Rep. 2019 Feb;71(1):42-47. doi: 10.1016/j.pharep.2018.08.001. Epub 2018 Aug 2.
18 Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression.J Clin Invest. 2013 Dec;123(12):5334-41. doi: 10.1172/JCI70395. Epub 2013 Nov 15.
19 The dynorphin/-opioid receptor system and its role in psychiatric disorders.Cell Mol Life Sci. 2012 Mar;69(6):857-96. doi: 10.1007/s00018-011-0844-x. Epub 2011 Oct 16.
20 Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: the role of mu opioid receptor activation.Pharmacol Biochem Behav. 2010 Jun;95(4):410-21. doi: 10.1016/j.pbb.2010.02.019. Epub 2010 Mar 15.
21 Dynorphinergic system alterations in the corticostriatal circuitry of neuropathic mice support its role in the negative affective component of pain.Genes Brain Behav. 2019 Jul;18(6):e12467. doi: 10.1111/gbb.12467. Epub 2018 Mar 15.
22 Preproenkephalin A-derived opioid peptides and mRNA of preproenkephalin A in human pheochromocytomas.Mol Cell Endocrinol. 1987 Jun;51(3):237-41. doi: 10.1016/0303-7207(87)90033-5.
23 Effect of dynorphin-(1-13) and related peptides on respiratory rate and morphine-induced respiratory rate depression.Eur J Pharmacol. 1983 Dec 9;96(1-2):117-22. doi: 10.1016/0014-2999(83)90537-x.
24 Characterization of human prodynorphin gene transcripts.Biochem Biophys Res Commun. 1995 Oct 24;215(3):881-8. doi: 10.1006/bbrc.1995.2546.
25 Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.J Neurol. 1999 Sep;246(9):789-97. doi: 10.1007/s004150050456.
26 Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am J Hum Genet. 2010 Nov 12;87(5):593-603. doi: 10.1016/j.ajhg.2010.10.001. Epub 2010 Oct 28.
27 The effect of 3,4-diaminopyridine on the patients with hereditary pure cerebellar ataxia.J Neurol Sci. 2010 May 15;292(1-2):81-4. doi: 10.1016/j.jns.2010.01.021. Epub 2010 Feb 23.
28 Peripheral endothelin B receptor agonist-induced antinociception involves endogenous opioids in mice.Pain. 2010 May;149(2):254-262. doi: 10.1016/j.pain.2010.02.009. Epub 2010 Mar 4.
29 Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence. Neurosci Lett. 2006 May 29;400(1-2):158-62. doi: 10.1016/j.neulet.2006.02.038. Epub 2006 Mar 9.
30 Dynorphin-based "release on demand" gene therapy for drug-resistant temporal lobe epilepsy.EMBO Mol Med. 2019 Oct;11(10):e9963. doi: 10.15252/emmm.201809963. Epub 2019 Sep 5.
31 Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E.Epigenetics. 2014 Aug;9(8):1184-93. doi: 10.4161/epi.29676. Epub 2014 Jul 7.
32 PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.Biochim Biophys Acta. 2014 Nov;1839(11):1226-32. doi: 10.1016/j.bbagrm.2014.09.001. Epub 2014 Sep 8.
33 Differential regulation of striatal preproenkephalin and preprotachykinin mRNA levels in MPTP-lesioned monkeys chronically treated with dopamine D1 or D2 receptor agonists.J Neurochem. 1999 Feb;72(2):682-92. doi: 10.1046/j.1471-4159.1999.0720682.x.
34 Gender-specific association of functional prodynorphin 68 bp repeats with cannabis exposure in an African American cohort.Neuropsychiatr Dis Treat. 2018 Apr 16;14:1025-1034. doi: 10.2147/NDT.S159954. eCollection 2018.
35 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
36 Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
37 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
38 Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
39 Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
40 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
41 The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line. FASEB J. 2008 Mar;22(3):662-70. doi: 10.1096/fj.07-8346com. Epub 2007 Oct 12.
42 Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
43 Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
44 Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
45 Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
46 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
47 Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence. Neurosci Lett. 2006 May 29;400(1-2):158-62. doi: 10.1016/j.neulet.2006.02.038. Epub 2006 Mar 9.