Details of Drug Off-Target (DOT)

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

• DOT Name: Hexokinase-3 (HK3)
• Synonyms: EC 2.7.1.1; Hexokinase type III; HK III; Hexokinase-C
• Gene Name: HK3
• Related Disease:
  Colorectal carcinoma
  Liver cirrhosis
  Neoplasm
  Promyelocytic leukaemia
  Uterine fibroids
• UniProt ID: HXK3_HUMAN
• PDB ID: 3HM8
• EC Number: 2.7.1.1
• Pfam ID: PF00349 ; PF03727
• Sequence:
  MDSIGSSGLRQGEETLSCSEEGLPGPSDSSELVQECLQQFKVTRAQLQQIQASLLGSMEQ
  ALRGQASPAPAVRMLPTYVGSTPHGTEQGDFVVLELGATGASLRVLWVTLTGIEGHRVEP
  RSQEFVIPQEVMLGAGQQLFDFAAHCLSEFLDAQPVNKQGLQLGFSFSFPCHQTGLDRST
  LISWTKGFRCSGVEGQDVVQLLRDAIRRQGAYNIDVVAVVNDTVGTMMGCEPGVRPCEVG
  LVVDTGTNACYMEEARHVAVLDEDRGRVCVSVEWGSFSDDGALGPVLTTFDHTLDHESLN
  PGAQRFEKMIGGLYLGELVRLVLAHLARCGVLFGGCTSPALLSQGSILLEHVAEMEDPST
  GAARVHAILQDLGLSPGASDVELVQHVCAAVCTRAAQLCAAALAAVLSCLQHSREQQTLQ
  VAVATGGRVCERHPRFCSVLQGTVMLLAPECDVSLIPSVDGGGRGVAMVTAVAARLAAHR
  RLLEETLAPFRLNHDQLAAVQAQMRKAMAKGLRGEASSLRMLPTFVRATPDGSERGDFLA
  LDLGGTNFRVLLVRVTTGVQITSEIYSIPETVAQGSGQQLFDHIVDCIVDFQQKQGLSGQ
  SLPLGFTFSFPCRQLGLDQGILLNWTKGFKASDCEGQDVVSLLREAITRRQAVELNVVAI
  VNDTVGTMMSCGYEDPRCEIGLIVGTGTNACYMEELRNVAGVPGDSGRMCINMEWGAFGD
  DGSLAMLSTRFDASVDQASINPGKQRFEKMISGMYLGEIVRHILLHLTSLGVLFRGQQIQ
  RLQTRDIFKTKFLSEIESDSLALRQVRAILEDLGLPLTSDDALMVLEVCQAVSQRAAQLC
  GAGVAAVVEKIRENRGLEELAVSVGVDGTLYKLHPRFSSLVAATVRELAPRCVVTFLQSE
  DGSGKGAALVTAVACRLAQLTRV
• Function: Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate.
• 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)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS08548-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[4]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[5]

2 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-3 (HK3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hexokinase-3 (HK3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hexokinase-3 (HK3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hexokinase-3 (HK3).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hexokinase-3 (HK3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Hexokinase-3 (HK3).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Hexokinase-3 (HK3).	[11]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Hexokinase-3 (HK3).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hexokinase-3 (HK3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hexokinase-3 (HK3).	[14]

References

• [1] Effect of lentivirus-mediated shRNA inactivation of HK1, HK2, and HK3 genes in colorectal cancer and melanoma cells.BMC Genet. 2016 Dec 22;17(Suppl 3):156. doi: 10.1186/s12863-016-0459-1.
• [2] Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis.Biochim Biophys Acta. 1998 Jan 8;1379(1):134-42. doi: 10.1016/s0304-4165(97)00092-5.
• [3] Multi-omics dataset to decipher the complexity of drug resistance in diffuse large B-cell lymphoma.Sci Rep. 2019 Jan 29;9(1):895. doi: 10.1038/s41598-018-37273-4.
• [4] PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells.Blood. 2012 May 24;119(21):4963-70. doi: 10.1182/blood-2011-09-378117. Epub 2012 Apr 12.
• [5] Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.Nat Commun. 2018 Sep 7;9(1):3636. doi: 10.1038/s41467-018-05428-6.
• [6] 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.
• [7] 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.
• [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] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] 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.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] 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.