Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR3Q0NN)

• DOT Name: Hexokinase-4 (GCK)
• Synonyms: HK4; EC 2.7.1.1; Glucokinase; Hexokinase type IV; HK IV; Hexokinase-D
• Gene Name: GCK
• Related Disease:
  Hyperinsulinism due to glucokinase deficiency
  Maturity-onset diabetes of the young type 2
  Monogenic diabetes
  Obsolete diabetes mellitus, noninsulin-dependent
  Permanent neonatal diabetes mellitus 1
  Transient neonatal diabetes mellitus
  Maturity-onset diabetes of the young
  Permanent neonatal diabetes mellitus
• UniProt ID: HXK4_HUMAN
• PDB ID: 1V4S ; 1V4T ; 3A0I ; 3F9M ; 3FGU ; 3FR0 ; 3GOI ; 3H1V ; 3ID8 ; 3IDH ; 3IMX ; 3QIC ; 3S41 ; 3VEV ; 3VEY ; 3VF6 ; 4DCH ; 4DHY ; 4ISE ; 4ISF ; 4ISG ; 4IWV ; 4IXC ; 4L3Q ; 4LC9 ; 4MLE ; 4MLH ; 4NO7 ; 4RCH ; 5V4W ; 5V4X ; 6E0E ; 6E0I ; 7T78 ; 7T79
• EC Number: 2.7.1.1
• Pfam ID: PF00349 ; PF03727
• Sequence:
  MLDDRARMEAAKKEKVEQILAEFQLQEEDLKKVMRRMQKEMDRGLRLETHEEASVKMLPT
  YVRSTPEGSEVGDFLSLDLGGTNFRVMLVKVGEGEEGQWSVKTKHQMYSIPEDAMTGTAE
  MLFDYISECISDFLDKHQMKHKKLPLGFTFSFPVRHEDIDKGILLNWTKGFKASGAEGNN
  VVGLLRDAIKRRGDFEMDVVAMVNDTVATMISCYYEDHQCEVGMIVGTGCNACYMEEMQN
  VELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRLVDESSANPGQQLYEKLIGGKYMGE
  LVRLVLLRLVDENLLFHGEASEQLRTRGAFETRFVSQVESDTGDRKQIYNILSTLGLRPS
  TTDCDIVRRACESVSTRAAHMCSAGLAGVINRMRESRSEDVMRITVGVDGSVYKLHPSFK
  ERFHASVRRLTPSCEITFIESEEGSGRGAALVSAVACKKACMLGQ
• Function: Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant. Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues. Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell. In pancreas, plays an important role in modulating insulin secretion. In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. Required to provide D-glucose 6-phosphate for the synthesis of glycogen. Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Galactose metabolism (hsa00052)
  Starch and sucrose metabolism (hsa00500)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Neomycin, ka.mycin and gentamicin biosynthesis (hsa00524)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of nucleotide sugars (hsa01250)
  Insulin sig.ling pathway (hsa04910)
  Insulin secretion (hsa04911)
  Prolactin sig.ling pathway (hsa04917)
  Glucagon sig.ling pathway (hsa04922)
  Type II diabetes mellitus (hsa04930)
  Maturity onset diabetes of the young (hsa04950)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Regulation of gene expression in beta cells (R-HSA-210745)
  Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) (R-HSA-5619073)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  Glycolysis (R-HSA-70171)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
• BioCyc Pathway: MetaCyc:HS02935-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperinsulinism due to glucokinase deficiency	DISHNQUZ	Definitive	Autosomal dominant	[1]
Maturity-onset diabetes of the young type 2	DISN6STS	Definitive	Autosomal dominant	[1]
Monogenic diabetes	DISEB8Q0	Definitive	Autosomal dominant	[2]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[3]
Permanent neonatal diabetes mellitus 1	DISL61PN	Strong	Autosomal recessive	[3]
Transient neonatal diabetes mellitus	DIST826V	Strong	Autosomal recessive	[3]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[4]
Permanent neonatal diabetes mellitus	DIS5AEXS	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Hexokinase-4 (GCK).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Hexokinase-4 (GCK).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Hexokinase-4 (GCK).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Hexokinase-4 (GCK).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Hexokinase-4 (GCK).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hexokinase-4 (GCK).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Hexokinase-4 (GCK).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Hexokinase-4 (GCK).	[11]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Hexokinase-4 (GCK).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Hexokinase-4 (GCK).	[13]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Hexokinase-4 (GCK).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hexokinase-4 (GCK).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [5] 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.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem Pharmacol. 2016 Jan 15;100:98-111.
• [12] A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3378-83.
• [13] Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism. J Biol Chem. 2011 Feb 25;286(8):6049-60. doi: 10.1074/jbc.M110.176842. Epub 2010 Dec 16.
• [14] 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.
• [15] Metabolomic modulations of HepG2 cells exposed to bisphenol analogues. Environ Int. 2019 Aug;129:59-67. doi: 10.1016/j.envint.2019.05.008. Epub 2019 May 20.