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
• 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]

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]

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]

References

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• [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.
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• [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.
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• [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.
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• [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.
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• [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.
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