Details of Drug Off-Target (DOT)

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

DOT Name	Glucokinase regulatory protein (GCKR)
Synonyms	GKRP; Glucokinase regulator
Gene Name	GCKR
Related Disease	Hepatitis B virus infection ( ) Nephropathy ( ) Neural tube defect ( ) Advanced cancer ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Atrial fibrillation ( ) Cardiac failure ( ) Cardiovascular disease ( ) Chronic kidney disease ( ) Chronic renal failure ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) Crohn disease ( ) End-stage renal disease ( ) Fatty liver disease ( ) Hepatitis C virus infection ( ) Hyperglycemia ( ) Insulinoma ( ) Maturity-onset diabetes of the young ( ) Metabolic disorder ( ) Myocardial infarction ( ) Myocardial ischemia ( ) Obesity ( ) Pancreatic cancer ( ) Polycystic ovarian syndrome ( ) Stroke ( ) Type-1/2 diabetes ( ) Alcohol dependence ( ) Alcohol-induced disorders ( ) Alcohol-related disorders ( ) Ankylosing spondylitis ( ) Gout ( ) Hepatitis ( ) Inflammatory bowel disease ( ) Maturity-onset diabetes of the young type 2 ( ) Monogenic diabetes ( ) Non-alcoholic fatty liver disease ( ) Psoriasis ( ) Sclerosing cholangitis ( ) Type-1 diabetes ( ) Ulcerative colitis ( ) Urolithiasis ( )
UniProt ID	GCKR_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4BB9; 4BBA; 4LY9; 4MQU; 4MRO; 4MSU; 4OHK; 4OHM; 4OHO; 4OHP; 4OLH; 4OP1; 4OP2; 4OP3; 4PX2; 4PX3; 4PX5; 4PXS
Pfam ID	PF20741
Sequence	MPGTKRFQHVIETPEPGKWELSGYEAAVPITEKSNPLTQDLDKADAENIVRLLGQCDAEI FQEEGQALSTYQRLYSESILTTMVQVAGKVQEVLKEPDGGLVVLSGGGTSGRMAFLMSVS FNQLMKGLGQKPLYTYLIAGGDRSVVASREGTEDSALHGIEELKKVAAGKKRVIVIGISV GLSAPFVAGQMDCCMNNTAVFLPVLVGFNPVSMARNDPIEDWSSTFRQVAERMQKMQEKQ KAFVLNPAIGPEGLSGSSRMKGGSATKILLETLLLAAHKTVDQGIAASQRCLLEILRTFE RAHQVTYSQSPKIATLMKSVSTSLEKKGHVYLVGWQTLGIIAIMDGVECIHTFGADFRDV RGFLIGDHSDMFNQKAELTNQGPQFTFSQEDFLTSILPSLTEIDTVVFIFTLDDNLTEVQ TIVEQVKEKTNHIQALAHSTVGQTLPIPLKKLFPSIISITWPLLFFEYEGNFIQKFQREL STKWVLNTVSTGAHVLLGKILQNHMLDLRISNSKLFWRALAMLQRFSGQSKARCIESLLR AIHFPQPLSDDIRAAPISCHVQVAHEKEQVIPIALLSLLFRCSITEAQAHLAAAPSVCEA VRSALAGPGQKRTADPLEILEPDVQ
Function	Regulates glucokinase (GCK) by forming an inactive complex with this enzyme. Acts by promoting GCK recruitment to the nucleus, possibly to provide a reserve of GCK that can be quickly released in the cytoplasm after a meal. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6-phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity.
Tissue Specificity	Found in liver and pancreas. Not detected in muscle, brain, heart, thymus, intestine, uterus, adipose tissue, kidney, adrenal, lung or spleen.
Reactome Pathway	Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107 ) Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[2]
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Cardiac failure	DISDC067	Strong	Genetic Variation	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[7]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[8]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[7]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[9]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[10]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[11]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[13]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[14]
Insulinoma	DISIU1JS	Strong	Altered Expression	[15]
Maturity-onset diabetes of the young	DISG75M5	Strong	Genetic Variation	[16]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[17]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[18]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[20]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[21]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[22]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[23]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[23]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[23]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[24]
Gout	DISHC0U7	Limited	Genetic Variation	[25]
Hepatitis	DISXXX35	Limited	Genetic Variation	[26]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[10]
Maturity-onset diabetes of the young type 2	DISN6STS	Limited	Biomarker	[27]
Monogenic diabetes	DISEB8Q0	Limited	Genetic Variation	[28]
Non-alcoholic fatty liver disease	DISDG1NL	Limited	Biomarker	[9]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[24]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[24]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[28]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[24]
Urolithiasis	DISNFTKT	Limited	Genetic Variation	[29]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

1 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 Glucokinase regulatory protein (GCKR).	[30]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucokinase regulatory protein (GCKR).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucokinase regulatory protein (GCKR).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glucokinase regulatory protein (GCKR).	[33]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glucokinase regulatory protein (GCKR).	[34]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Glucokinase regulatory protein (GCKR).	[35]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glucokinase regulatory protein (GCKR).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glucokinase regulatory protein (GCKR).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glucokinase regulatory protein (GCKR).	[38]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Glucokinase regulatory protein (GCKR).	[39]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Glucokinase regulatory protein (GCKR).	[34]
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⏷ Show the Full List of 10 Drug(s)

References

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3	Association between maternal single nucleotide polymorphisms in genes regulating glucose metabolism and risk for neural tube defects in offspring.Birth Defects Res A Clin Mol Teratol. 2015 Jun;103(6):471-8. doi: 10.1002/bdra.23332. Epub 2014 Nov 5.
4	Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
5	GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study.Diabet Med. 2016 Jul;33(7):968-75. doi: 10.1111/dme.12971. Epub 2015 Oct 30.
6	Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
7	Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: A systematic review and meta-analysis.PLoS One. 2018 Oct 23;13(10):e0206174. doi: 10.1371/journal.pone.0206174. eCollection 2018.
8	Identification of CDC42BPG as a novel susceptibility locus for hyperuricemia in a Japanese population.Mol Genet Genomics. 2018 Apr;293(2):371-379. doi: 10.1007/s00438-017-1394-1. Epub 2017 Nov 9.
9	Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality.Diabetologia. 2020 Feb;63(2):253-260. doi: 10.1007/s00125-019-05024-3. Epub 2019 Nov 11.
10	Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
11	Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.PLoS Genet. 2011 Sep;7(9):e1002292. doi: 10.1371/journal.pgen.1002292. Epub 2011 Sep 29.
12	NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects.Hum Mol Genet. 2018 Jun 15;27(12):2214-2223. doi: 10.1093/hmg/ddy124.
13	A genetic screen identifies interferon- effector genes required to suppress hepatitis C virus replication.Gastroenterology. 2013 Jun;144(7):1438-49, 1449.e1-9. doi: 10.1053/j.gastro.2013.02.026. Epub 2013 Feb 24.
14	Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients.Metabolism. 2018 Dec;89:8-17. doi: 10.1016/j.metabol.2018.09.004. Epub 2018 Sep 23.
15	When a Little Bit More Makes the Difference: Expression Levels of GKRP Determines the Subcellular Localization of GK in Tanycytes.Front Neurosci. 2019 Mar 29;13:275. doi: 10.3389/fnins.2019.00275. eCollection 2019.
16	Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study.Am J Hum Genet. 2008 May;82(5):1185-92. doi: 10.1016/j.ajhg.2008.03.015. Epub 2008 Apr 24.
17	An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels.Diabetes. 2017 Jun;66(6):1723-1728. doi: 10.2337/db16-1384. Epub 2017 Apr 6.
18	TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):451-7. doi: 10.1161/ATVBAHA.110.216333. Epub 2010 Nov 11.
19	Lipid regulatory genes polymorphism in children with and without obesity and cardiometabolic risk factors: The CASPIAN-III study.J Res Med Sci. 2018 Feb 20;23:11. doi: 10.4103/jrms.JRMS_911_17. eCollection 2018.
20	Genes related to diabetes may be associated with pancreatic cancer in a population-based case-control study in Minnesota.Pancreas. 2012 Jan;41(1):50-3. doi: 10.1097/MPA.0b013e3182247625.
21	Association between copy-number variation on metabolic phenotypes and HDL-C levels in patients with polycystic ovary syndrome.Mol Biol Rep. 2017 Feb;44(1):51-61. doi: 10.1007/s11033-016-4080-1. Epub 2016 Nov 22.
22	Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.Nat Commun. 2019 Sep 11;10(1):4130. doi: 10.1038/s41467-019-11576-0.
23	Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations.Nat Commun. 2019 Apr 2;10(1):1499. doi: 10.1038/s41467-019-09480-8.
24	Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
25	Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.Nat Genet. 2019 Oct;51(10):1459-1474. doi: 10.1038/s41588-019-0504-x. Epub 2019 Oct 2.
26	Genetics of nonalcoholic fatty liver disease.Metabolism. 2016 Aug;65(8):1026-37. doi: 10.1016/j.metabol.2015.08.018. Epub 2015 Sep 1.
27	From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation.Diabetes. 2006 Jun;55(6):1713-22. doi: 10.2337/db05-1513.
28	Genetic variability of GCKR alters lipid profiles in children with monogenic and autoimmune diabetes.Exp Clin Endocrinol Diabetes. 2014 Oct;122(9):503-9. doi: 10.1055/s-0034-1375648. Epub 2014 Jun 11.
29	Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.
30	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.
31	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.
32	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
33	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
34	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.
35	A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
36	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
37	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
38	Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
39	Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.