Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS4HE8E)

• DOT Name: GATOR1 complex protein NPRL3 (NPRL3)
• Synonyms: -14 gene protein; Alpha-globin regulatory element-containing gene protein; Nitrogen permease regulator 3-like protein; Protein CGTHBA
• Gene Name: NPRL3
• Related Disease:
  Focal epilepsy
  Macular corneal dystrophy
  Alpha thalassemia
  Epilepsy, familial focal, with variable foci 3
  Non-insulin dependent diabetes
  Sickle-cell anaemia
  Fleck corneal dystrophy
  Familial focal epilepsy with variable foci
  Progressive familial heart block, type 1A
  Neuroblastoma
  Thalassemia
• UniProt ID: NPRL3_HUMAN
• PDB ID: 6CES; 6CET; 7T3A; 7T3B; 7T3C; 8FW5
• Pfam ID: PF03666
• Sequence:
  MRDNTSPISVILVSSGSRGNKLLFRYPFQRSQEHPASQTSKPRSRYAASNTGDHADEQDG
  DSRFSDVILATILATKSEMCGQKFELKIDNVRFVGHPTLLQHALGQISKTDPSPKREAPT
  MILFNVVFALRANADPSVINCLHNLSRRIATVLQHEERRCQYLTREAKLILALQDEVSAM
  ADGNEGPQSPFHHILPKCKLARDLKEAYDSLCTSGVVRLHINSWLEVSFCLPHKIHYAAS
  SLIPPEAIERSLKAIRPYHALLLLSDEKSLLGELPIDCSPALVRVIKTTSAVKNLQQLAQ
  DADLALLQVFQLAAHLVYWGKAIIIYPLCENNVYMLSPNASVCLYSPLAEQFSHQFPSHD
  LPSVLAKFSLPVSLSEFRNPLAPAVQETQLIQMVVWMLQRRLLIQLHTYVCLMASPSEEE
  PRPREDDVPFTARVGGRSLSTPNALSFGSPTSSDDMTLTSPSMDNSSAELLPSGDSPLNQ
  RMTENLLASLSEHERAAILSVPAAQNPEDLRMFARLLHYFRGRHHLEEIMYNENTRRSQL
  LMLFDKFRSVLVVTTHEDPVIAVFQALLP
• Function: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway.
• Tissue Specificity: Widely expressed. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes .
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Focal epilepsy	DIS4LY5L	Definitive	Autosomal dominant	[1]
Macular corneal dystrophy	DISOLD0H	Definitive	Genetic Variation	[2]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[3]
Epilepsy, familial focal, with variable foci 3	DISX25F4	Strong	Autosomal dominant	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[5]
Sickle-cell anaemia	DIS5YNZB	Strong	Genetic Variation	[6]
Fleck corneal dystrophy	DISERQJ1	moderate	Biomarker	[7]
Familial focal epilepsy with variable foci	DIS50BKW	Supportive	Autosomal dominant	[8]
Progressive familial heart block, type 1A	DISUPY6A	Disputed	Biomarker	[9]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]
Thalassemia	DIS76XZB	Limited	Biomarker	[6]

8 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 GATOR1 complex protein NPRL3 (NPRL3).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of GATOR1 complex protein NPRL3 (NPRL3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GATOR1 complex protein NPRL3 (NPRL3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of GATOR1 complex protein NPRL3 (NPRL3).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of GATOR1 complex protein NPRL3 (NPRL3).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GATOR1 complex protein NPRL3 (NPRL3).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of GATOR1 complex protein NPRL3 (NPRL3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of GATOR1 complex protein NPRL3 (NPRL3).	[20]

2 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 GATOR1 complex protein NPRL3 (NPRL3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GATOR1 complex protein NPRL3 (NPRL3).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations.Epilepsia. 2019 Nov;60(11):2163-2173. doi: 10.1111/epi.16370. Epub 2019 Oct 17.
• [3] alpha-thalassemia resulting from a negative chromosomal position effect.Blood. 2000 Aug 1;96(3):800-7.
• [4] Nprl3 is required for normal development of the cardiovascular system. Mamm Genome. 2012 Aug;23(7-8):404-15. doi: 10.1007/s00335-012-9398-y. Epub 2012 Apr 27.
• [5] Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.Science. 2007 Jun 1;316(5829):1331-6. doi: 10.1126/science.1142358. Epub 2007 Apr 26.
• [6] Genetic determinants of haemolysis in sickle cell anaemia.Br J Haematol. 2013 Apr;161(2):270-8. doi: 10.1111/bjh.12245. Epub 2013 Feb 14.
• [7] Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy.Neurobiol Dis. 2020 Feb;134:104640. doi: 10.1016/j.nbd.2019.104640. Epub 2019 Oct 19.
• [8] Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016 Jan;79(1):120-31. doi: 10.1002/ana.24547. Epub 2015 Dec 12.
• [9] Arrhythmic Burden as Determined by Ambulatory Continuous Cardiac Monitoring in Patients With New-Onset Persistent Left Bundle Branch Block Following Transcatheter Aortic ValveReplacement: The MARE Study.JACC Cardiovasc Interv. 2018 Aug 13;11(15):1495-1505. doi: 10.1016/j.jcin.2018.04.016. Epub 2018 Jul 18.
• [10] DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons.Neurobiol Dis. 2018 Jun;114:184-193. doi: 10.1016/j.nbd.2018.02.013. Epub 2018 Feb 24.
• [11] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] 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.
• [20] 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.