Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMPHE8O)

• DOT Name: Hexokinase-1 (HK1)
• Synonyms: EC 2.7.1.1; Brain form hexokinase; Hexokinase type I; HK I; Hexokinase-A
• Gene Name: HK1
• Related Disease:
  Neurodevelopmental disorder with visual defects and brain anomalies
  Non-spherocytic hemolytic anemia due to hexokinase deficiency
  Retinitis pigmentosa 79
  Charcot-Marie-Tooth disease type 4G
• UniProt ID: HXK1_HUMAN
• PDB ID: 1CZA; 1DGK; 1HKB; 1HKC; 1QHA; 4F9O; 4FOE; 4FOI; 4FPA; 4FPB
• EC Number: 2.7.1.1
• Pfam ID: PF00349 ; PF03727
• Sequence:
  MIAAQLLAYYFTELKDDQVKKIDKYLYAMRLSDETLIDIMTRFRKEMKNGLSRDFNPTAT
  VKMLPTFVRSIPDGSEKGDFIALDLGGSSFRILRVQVNHEKNQNVHMESEVYDTPENIVH
  GSGSQLFDHVAECLGDFMEKRKIKDKKLPVGFTFSFPCQQSKIDEAILITWTKRFKASGV
  EGADVVKLLNKAIKKRGDYDANIVAVVNDTVGTMMTCGYDDQHCEVGLIIGTGTNACYME
  ELRHIDLVEGDEGRMCINTEWGAFGDDGSLEDIRTEFDREIDRGSLNPGKQLFEKMVSGM
  YLGELVRLILVKMAKEGLLFEGRITPELLTRGKFNTSDVSAIEKNKEGLHNAKEILTRLG
  VEPSDDDCVSVQHVCTIVSFRSANLVAATLGAILNRLRDNKGTPRLRTTVGVDGSLYKTH
  PQYSRRFHKTLRRLVPDSDVRFLLSESGSGKGAAMVTAVAYRLAEQHRQIEETLAHFHLT
  KDMLLEVKKRMRAEMELGLRKQTHNNAVVKMLPSFVRRTPDGTENGDFLALDLGGTNFRV
  LLVKIRSGKKRTVEMHNKIYAIPIEIMQGTGEELFDHIVSCISDFLDYMGIKGPRMPLGF
  TFSFPCQQTSLDAGILITWTKGFKATDCVGHDVVTLLRDAIKRREEFDLDVVAVVNDTVG
  TMMTCAYEEPTCEVGLIVGTGSNACYMEEMKNVEMVEGDQGQMCINMEWGAFGDNGCLDD
  IRTHYDRLVDEYSLNAGKQRYEKMISGMYLGEIVRNILIDFTKKGFLFRGQISETLKTRG
  IFETKFLSQIESDRLALLQVRAILQQLGLNSTCDDSILVKTVCGVVSRRAAQLCGAGMAA
  VVDKIRENRGLDRLNVTVGVDGTLYKLHPHFSRIMHQTVKELSPKCNVSFLLSEDGSGKG
  AALITAVGVRLRTEASS
• Function: Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively). Does not phosphorylate N-acetyl-D-glucosamine. Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate. Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan. When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome.
• Tissue Specificity: Isoform 2: Erythrocyte specific (Ref.6). Isoform 3: Testis-specific . Isoform 4: Testis-specific .
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Fructose and mannose metabolism (hsa00051)
  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)
  HIF-1 sig.ling pathway (hsa04066)
  Insulin sig.ling pathway (hsa04910)
  Type II diabetes mellitus (hsa04930)
  Carbohydrate digestion and absorption (hsa04973)
  Shigellosis (hsa05131)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Glycolysis (R-HSA-70171)
  Defective HK1 causes hexokinase deficiency (HK deficiency) (R-HSA-5619056)
• BioCyc Pathway: MetaCyc:HS08136-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with visual defects and brain anomalies	DISCM9U2	Strong	Autosomal dominant	[1]
Non-spherocytic hemolytic anemia due to hexokinase deficiency	DISTEMCR	Strong	Autosomal recessive	[2]
Retinitis pigmentosa 79	DISWKKB9	Strong	Autosomal dominant	[3]
Charcot-Marie-Tooth disease type 4G	DISPT2N2	Supportive	Autosomal recessive	[4]

3 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-1 (HK1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Hexokinase-1 (HK1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hexokinase-1 (HK1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hexokinase-1 (HK1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hexokinase-1 (HK1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Hexokinase-1 (HK1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hexokinase-1 (HK1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Hexokinase-1 (HK1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hexokinase-1 (HK1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Hexokinase-1 (HK1).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Hexokinase-1 (HK1).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Hexokinase-1 (HK1).	[15]
Mebendazole	DMO14SG	Approved	Mebendazole decreases the expression of Hexokinase-1 (HK1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hexokinase-1 (HK1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Hexokinase-1 (HK1).	[18]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Hexokinase-1 (HK1).	[19]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone increases the expression of Hexokinase-1 (HK1).	[20]

References

• [1] De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment. Eur J Hum Genet. 2019 Jul;27(7):1081-1089. doi: 10.1038/s41431-019-0366-9. Epub 2019 Feb 18.
• [2] Homozygous intragenic deletion of type I hexokinase gene causes lethal hemolytic anemia of the affected fetus. Blood. 2002 Sep 1;100(5):1930. doi: 10.1182/blood-2002-05-1599.
• [3] A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Sep 4;55(11):7147-58. doi: 10.1167/iovs.14-15419.
• [4] A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR). Eur J Hum Genet. 2009 Dec;17(12):1606-14. doi: 10.1038/ejhg.2009.99. Epub 2009 Jun 17.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] 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.
• [11] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] 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.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death. Toxicol Appl Pharmacol. 2023 Sep 15;475:116630. doi: 10.1016/j.taap.2023.116630. Epub 2023 Jul 18.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [20] 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol Sci. 2013 Mar;132(1):235-49.