Details of Drug Off-Target (DOT)

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

• DOT Name: Hexokinase HKDC1 (HKDC1)
• Synonyms: EC 2.7.1.1; Hexokinase domain-containing protein 1
• Gene Name: HKDC1
• UniProt ID: HKDC1_HUMAN
• EC Number: 2.7.1.1
• Pfam ID: PF00349 ; PF03727
• Sequence:
  MFAVHLMAFYFSKLKEDQIKKVDRFLYHMRLSDDTLLDIMRRFRAEMEKGLAKDTNPTAA
  VKMLPTFVRAIPDGSENGEFLSLDLGGSKFRVLKVQVAEEGKRHVQMESQFYPTPNEIIR
  GNGTELFEYVADCLADFMKTKDLKHKKLPLGLTFSFPCRQTKLEEGVLLSWTKKFKARGV
  QDTDVVSRLTKAMRRHKDMDVDILALVNDTVGTMMTCAYDDPYCEVGVIIGTGTNACYME
  DMSNIDLVEGDEGRMCINTEWGAFGDDGALEDIRTEFDRELDLGSLNPGKQLFEKMISGL
  YLGELVRLILLKMAKAGLLFGGEKSSALHTKGKIETRHVAAMEKYKEGLANTREILVDLG
  LEPSEADCIAVQHVCTIVSFRSANLCAAALAAILTRLRENKKVERLRTTVGMDGTLYKIH
  PQYPKRLHKVVRKLVPSCDVRFLLSESGSTKGAAMVTAVASRVQAQRKQIDRVLALFQLT
  REQLVDVQAKMRAELEYGLKKKSHGLATVRMLPTYVCGLPDGTEKGKFLALDLGGTNFRV
  LLVKIRSGRRSVRMYNKIFAIPLEIMQGTGEELFDHIVQCIADFLDYMGLKGASLPLGFT
  FSFPCRQMSIDKGTLIGWTKGFKATDCEGEDVVDMLREAIKRRNEFDLDIVAVVNDTVGT
  MMTCGYEDPNCEIGLIAGTGSNMCYMEDMRNIEMVEGGEGKMCINTEWGGFGDNGCIDDI
  WTRYDTEVDEGSLNPGKQRYEKMTSGMYLGEIVRQILIDLTKQGLLFRGQISERLRTRGI
  FETKFLSQIESDRLALLQVRRILQQLGLDSTCEDSIVVKEVCGAVSRRAAQLCGAGLAAI
  VEKRREDQGLEHLRITVGVDGTLYKLHPHFSRILQETVKELAPRCDVTFMLSEDGSGKGA
  ALITAVAKRLQQAQKEN
• Function: Catalyzes the phosphorylation of hexose to hexose 6-phosphate, although at very low level compared to other hexokinases. Has low glucose phosphorylating activity compared to other hexokinases. Involved in glucose homeostasis and hepatic lipid accumulation. Required to maintain whole-body glucose homeostasis during pregnancy; however additional evidences are required to confirm this role.
• Tissue Specificity: Widely expressed . Highly expressed in the brush border, surface epithelium and the myenteric plexus of the small and large intestines; the acinar centrocytes and interlobular ducts of the pancreas; and the alveolar macrophages in the lungs (at protein level) . Present at moderate level in the thyroid follicular epithelium (at protein level) .
• 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)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Hexokinase HKDC1 (HKDC1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hexokinase HKDC1 (HKDC1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hexokinase HKDC1 (HKDC1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Hexokinase HKDC1 (HKDC1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hexokinase HKDC1 (HKDC1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hexokinase HKDC1 (HKDC1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hexokinase HKDC1 (HKDC1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Hexokinase HKDC1 (HKDC1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Hexokinase HKDC1 (HKDC1).	[9]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Hexokinase HKDC1 (HKDC1).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Hexokinase HKDC1 (HKDC1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hexokinase HKDC1 (HKDC1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hexokinase HKDC1 (HKDC1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hexokinase HKDC1 (HKDC1).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Hexokinase HKDC1 (HKDC1).	[14]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Hexokinase HKDC1 (HKDC1).	[15]

References

• [1] 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.
• [2] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [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] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [14] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [15] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.