Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMC1O66)

• DOT Name: Protein lifeguard 1 (GRINA)
• Synonyms: Glutamate receptor-associated protein 1; NMDA receptor glutamate-binding subunit; Putative MAPK-activating protein PM02; Transmembrane BAX inhibitor motif-containing protein 3
• Gene Name: GRINA
• Related Disease:
  Coeliac disease
  Huntington disease
  Gastric cancer
  Osteoarthritis
  Stomach cancer
  Stroke
• UniProt ID: LFG1_HUMAN
• Pfam ID: PF01027
• Sequence:
  MSHEKSFLVSGDNYPPPNPGYPGGPQPPMPPYAQPPYPGAPYPQPPFQPSPYGQPGYPHG
  PSPYPQGGYPQGPYPQGGYPQGPYPQEGYPQGPYPQGGYPQGPYPQSPFPPNPYGQPQVF
  PGQDPDSPQHGNYQEEGPPSYYDNQDFPATNWDDKSIRQAFIRKVFLVLTLQLSVTLSTV
  SVFTFVAEVKGFVRENVWTYYVSYAVFFISLIVLSCCGDFRRKHPWNLVALSVLTASLSY
  MVGMIASFYNTEAVIMAVGITTAVCFTVVIFSMQTRYDFTSCMGVLLVSMVVLFIFAILC
  IFIRNRILEIVYASLGALLFTCFLAVDTQLLLGNKQLSLSPEEYVFAALNLYTDIINIFL
  YILTIIGRAKE
• Function: Potential apoptotic regulator.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coeliac disease	DISIY60C	Strong	Biomarker	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Limited	Biomarker	[3]
Osteoarthritis	DIS05URM	Limited	Biomarker	[4]
Stomach cancer	DISKIJSX	Limited	Biomarker	[3]
Stroke	DISX6UHX	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein lifeguard 1 (GRINA).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein lifeguard 1 (GRINA).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein lifeguard 1 (GRINA).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein lifeguard 1 (GRINA).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein lifeguard 1 (GRINA).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein lifeguard 1 (GRINA).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein lifeguard 1 (GRINA).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Protein lifeguard 1 (GRINA).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein lifeguard 1 (GRINA).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein lifeguard 1 (GRINA).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Protein lifeguard 1 (GRINA).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein lifeguard 1 (GRINA).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein lifeguard 1 (GRINA).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein lifeguard 1 (GRINA).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein lifeguard 1 (GRINA).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein lifeguard 1 (GRINA).	[14]

References

• [1] Extraintestinal manifestations of celiac disease: 33-mer gliadin binding to glutamate receptor GRINA as a new explanation.Bioessays. 2016 May;38(5):427-39. doi: 10.1002/bies.201500143. Epub 2016 Mar 18.
• [2] Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively.Genomics. 1993 Jul;17(1):237-9. doi: 10.1006/geno.1993.1311.
• [3] Transmembrane protein GRINA modulates aerobic glycolysis and promotes tumor progression in gastric cancer.J Exp Clin Cancer Res. 2018 Dec 12;37(1):308. doi: 10.1186/s13046-018-0974-1.
• [4] Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci.Arthritis Rheumatol. 2019 Aug;71(8):1285-1296. doi: 10.1002/art.40849. Epub 2019 Jun 27.
• [5] EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia.Int J Mol Sci. 2019 Oct 31;20(21):5421. doi: 10.3390/ijms20215421.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] 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.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [17] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.