Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHZF6ZV)

• DOT Name: G-protein coupled receptor 39 (GPR39)
• Gene Name: GPR39
• UniProt ID: GPR39_HUMAN
• Pfam ID: PF00001
• Sequence:
  MASPSLPGSDCSQIIDHSHVPEFEVATWIKITLILVYLIIFVMGLLGNSATIRVTQVLQK
  KGYLQKEVTDHMVSLACSDILVFLIGMPMEFYSIIWNPLTTSSYTLSCKLHTFLFEACSY
  ATLLHVLTLSFERYIAICHPFRYKAVSGPCQVKLLIGFVWVTSALVALPLLFAMGTEYPL
  VNVPSHRGLTCNRSSTRHHEQPETSNMSICTNLSSRWTVFQSSIFGAFVVYLVVLLSVAF
  MCWNMMQVLMKSQKGSLAGGTRPPQLRKSESEESRTARRQTIIFLRLIVVTLAVCWMPNQ
  IRRIMAAAKPKHDWTRSYFRAYMILLPFSETFFYLSSVINPLLYTVSSQQFRRVFVQVLC
  CRLSLQHANHEKRLRVHAHSTTDSARFVQRPLLFASRRQSSARRTEKIFLSTFQSEAEPQ
  SKSQSLSLESLEPNSGAKPANSAAENGFQEHEV
• Function: Zinc-sensing receptor that can sense changes in extracellular Zn(2+), mediate Zn(2+) signal transmission, and participates in the regulation of numerous physiological processes including glucose homeostasis regulation, gastrointestinal mobility, hormone secretion and cell death. Activation by Zn(2+) in keratinocytes increases the intracellular concentration of Ca(2+) and activates the ERK/MAPK and PI3K/AKT signaling pathways leading to epithelial repair. Plays an essential role in normal wound healing by inducing the production of cytokines including the major inflammatory cytokine IL6 via the PKC/MAPK/CEBPB pathway. Regulates adipose tissue metabolism, especially lipolysis, and regulates the function of lipases, such as hormone-sensitive lipase and adipose triglyceride lipase. Plays a role in the inhibition of cell death and protects against oxidative, endoplasmic reticulum and mitochondrial stress by inducing secretion of the cytoprotective pigment epithelium-derived growth factor (PEDF) and probably other protective transcripts in a GNA13/RHOA/SRE-dependent manner. Forms dynamic heteroreceptor complexes with HTR1A and GALR1 depending on cell type or specific physiological states, resulting in signaling diversity: HTR1A-GPR39 shows additive increase in signaling along the serum response element (SRE) and NF-kappa-B pathways while GALR1 acts as an antagonist blocking SRE.
• Tissue Specificity: Expressed in many tissues, including the stomach, intestine and hypothalamus.
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (s) signalling events (R-HSA-418555)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of G-protein coupled receptor 39 (GPR39).	[1]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of G-protein coupled receptor 39 (GPR39).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G-protein coupled receptor 39 (GPR39).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G-protein coupled receptor 39 (GPR39).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of G-protein coupled receptor 39 (GPR39).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of G-protein coupled receptor 39 (GPR39).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of G-protein coupled receptor 39 (GPR39).	[7]

References

• [1] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [4] 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.
• [5] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [6] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.