Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7FVO3Z)

• DOT Name: Choline kinase alpha (CHKA)
• Synonyms: CK; EC 2.7.1.32; CHETK-alpha; Ethanolamine kinase; EK; EC 2.7.1.82
• Gene Name: CHKA
• Related Disease: Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures
• UniProt ID: CHKA_HUMAN
• PDB ID: 2CKO; 2CKP; 2CKQ; 2I7Q; 3F2R; 3G15; 3ZM9; 4BR3; 4CG8; 4CG9; 4CGA; 4DA5; 5AFV; 5EQE; 5EQP; 5EQY; 5FTG; 5FUT; 5W6O; 7A04; 7A06; 7NB1; 7NB2; 7NB3; 8BI5; 8BI6
• EC Number: 2.7.1.32; 2.7.1.82
• Pfam ID: PF01633
• Sequence:
  MKTKFCTGGEAEPSPLGLLLSCGSGSAAPAPGVGQQRDAASDLESKQLGGQQPPLALPPP
  PPLPLPLPLPQPPPPQPPADEQPEPRTRRRAYLWCKEFLPGAWRGLREDEFHISVIRGGL
  SNMLFQCSLPDTTATLGDEPRKVLLRLYGAILQMRSCNKEGSEQAQKENEFQGAEAMVLE
  SVMFAILAERSLGPKLYGIFPQGRLEQFIPSRRLDTEELSLPDISAEIAEKMATFHGMKM
  PFNKEPKWLFGTMEKYLKEVLRIKFTEESRIKKLHKLLSYNLPLELENLRSLLESTPSPV
  VFCHNDCQEGNILLLEGRENSEKQKLMLIDFEYSSYNYRGFDIGNHFCEWMYDYSYEKYP
  FFRANIRKYPTKKQQLHFISSYLPAFQNDFENLSTEEKSIIKEEMLLEVNRFALASHFLW
  GLWSIVQAKISSIEFGYMDYAQARFDAYFHQKRKLGV
• Function: Plays a key role in phospholipid biosynthesis by catalyzing the phosphorylation of free choline to phosphocholine, the first step in phosphatidylcholine biosynthesis. Also phosphorylates ethanolamine, thereby contributing to phosphatidylethanolamine biosynthesis. Has higher activity with choline. May contribute to tumor cell growth ; [Isoform 1]: This isoform plays a key role in lipolysis of lipid droplets following glucose deprivation. In response to glucose deprivation, phosphorylated by AMPK, promoting localization to lipid droplets. Phosphorylation is followed by acetylation by KAT5, leading to dissociation of the homodimer into a monomer. Monomeric CHKA isoform 1 is converted into a tyrosine-protein kinase, which phosphorylates lipid droplet structural proteins PLIN2 and PLIN3, leading to lipolysis of lipid droplets.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Synthesis of PE (R-HSA-1483213)
  Synthesis of PC (R-HSA-1483191)
• BioCyc Pathway: MetaCyc:HS03334-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures	DIS0IVAI	Strong	Autosomal recessive	[1]

24 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 Choline kinase alpha (CHKA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Choline kinase alpha (CHKA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Choline kinase alpha (CHKA).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Choline kinase alpha (CHKA).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Choline kinase alpha (CHKA).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Choline kinase alpha (CHKA).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Choline kinase alpha (CHKA).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Choline kinase alpha (CHKA).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Choline kinase alpha (CHKA).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Choline kinase alpha (CHKA).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Choline kinase alpha (CHKA).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Choline kinase alpha (CHKA).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Choline kinase alpha (CHKA).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Choline kinase alpha (CHKA).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Choline kinase alpha (CHKA).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Choline kinase alpha (CHKA).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Choline kinase alpha (CHKA).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Choline kinase alpha (CHKA).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Choline kinase alpha (CHKA).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Choline kinase alpha (CHKA).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Choline kinase alpha (CHKA).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Choline kinase alpha (CHKA).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Choline kinase alpha (CHKA).	[22]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Choline kinase alpha (CHKA).	[23]

References

• [1] Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly. Brain. 2022 Jun 30;145(6):1916-1923. doi: 10.1093/brain/awac074.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells. Arch Toxicol. 2018 Feb;92(2):935-951. doi: 10.1007/s00204-017-2102-y. Epub 2017 Nov 6.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action. Arch Toxicol. 2021 Jan;95(1):321-336. doi: 10.1007/s00204-020-02902-3. Epub 2020 Sep 10.
• [23] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.