Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7A2FE8)

• DOT Name: G-protein coupled receptor 83 (GPR83)
• Synonyms: G-protein coupled receptor 72
• Gene Name: GPR83
• Related Disease:
  Hyperinsulinemic hypoglycemia
  Drug dependence
  Hyperinsulinemia
  Obesity
  Polycystic ovarian syndrome
  Immune system disorder
• UniProt ID: GPR83_HUMAN
• Pfam ID: PF00001
• Sequence:
  MVPHLLLLCLLPLVRATEPHEGRADEQSAEAALAVPNASHFFSWNNYTFSDWQNFVGRRR
  YGAESQNPTVKALLIVAYSFIIVFSLFGNVLVCHVIFKNQRMHSATSLFIVNLAVADIMI
  TLLNTPFTLVRFVNSTWIFGKGMCHVSRFAQYCSLHVSALTLTAIAVDRHQVIMHPLKPR
  ISITKGVIYIAVIWTMATFFSLPHAICQKLFTFKYSEDIVRSLCLPDFPEPADLFWKYLD
  LATFILLYILPLLIISVAYARVAKKLWLCNMIGDVTTEQYFALRRKKKKTIKMLMLVVVL
  FALCWFPLNCYVLLLSSKVIRTNNALYFAFHWFAMSSTCYNPFIYCWLNENFRIELKALL
  SMCQRPPKPQEDRPPSPVPSFRVAWTEKNDGQRAPLANNLLPTSQLQSGKTDLSSVEPIV
  TMS
• Function: G-protein coupled receptor for PEN, a neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)- and G(q)-alpha-alpha-mediated pathway in response to PEN. Plays a role in food intake and body weight regulation. May contribute to the regulation of anxiety-related behaviors.
• Tissue Specificity: Highly expressed in the brain and spinal cord, and found in lower concentrations in the thymus and other tissues.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperinsulinemic hypoglycemia	DIS3KP5D	Definitive	Altered Expression	[1]
Drug dependence	DIS9IXRC	Strong	Biomarker	[2]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[5]
Immune system disorder	DISAEGPH	moderate	Altered Expression	[6]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of G-protein coupled receptor 83 (GPR83).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G-protein coupled receptor 83 (GPR83).	[11]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of G-protein coupled receptor 83 (GPR83).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of G-protein coupled receptor 83 (GPR83).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of G-protein coupled receptor 83 (GPR83).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of G-protein coupled receptor 83 (GPR83).	[12]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of G-protein coupled receptor 83 (GPR83).	[13]

References

• [1] Transient neonatal hyperinsulinaemic hypoglycaemia: perinatal predictors of length and cost of stay.Eur J Pediatr. 2018 Dec;177(12):1823-1829. doi: 10.1007/s00431-018-3242-7. Epub 2018 Sep 19.
• [2] Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation.ACS Chem Neurosci. 2019 Apr 17;10(4):1884-1891. doi: 10.1021/acschemneuro.8b00559. Epub 2019 Feb 21.
• [3] Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-1 gene.Horm Res. 1999;52(5):230-4. doi: 10.1159/000023466.
• [4] The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms.Nat Commun. 2013;4:1968. doi: 10.1038/ncomms2968.
• [5] Exploring factors related to changes in body composition, insulin sensitivity and aerobic capacity in response to a 12-week exercise intervention in overweight and obese women with and without polycystic ovary syndrome.PLoS One. 2017 Aug 3;12(8):e0182412. doi: 10.1371/journal.pone.0182412. eCollection 2017.
• [6] Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders.Prog Mol Biol Transl Sci. 2018;159:1-25. doi: 10.1016/bs.pmbts.2018.07.002. Epub 2018 Aug 25.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [13] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.