Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK2YRA0)

• DOT Name: Glycerol kinase (GK)
• Synonyms: Glycerokinase; EC 2.7.1.30; ATP:glycerol 3-phosphotransferase
• Gene Name: GK
• Related Disease:
  Becker muscular dystrophy
  Inborn glycerol kinase deficiency
  Aland island eye disease
  Duchenne muscular dystrophy
  Galactokinase deficiency
  Hypogonadism
  Hypogonadotropic hypogonadism
  Inborn error of metabolism
  Klinefelter syndrome
  Myocardial ischemia
  Obesity
  Retinitis pigmentosa
  Tuberculosis
  Type-1/2 diabetes
  Familial hypercholesterolemia
  X-linked adrenal hypoplasia congenita
  Intellectual disability
  Non-insulin dependent diabetes
• UniProt ID: GLPK_HUMAN
• EC Number: 2.7.1.30
• Pfam ID: PF02782 ; PF00370
• Sequence:
  MAASKKAVLGPLVGAVDQGTSSTRFLVFNSKTAELLSHHQVEIKQEFPREGWVEQDPKEI
  LHSVYECIEKTCEKLGQLNIDISNIKAIGVSNQRETTVVWDKITGEPLYNAVVWLDLRTQ
  STVESLSKRIPGNNNFVKSKTGLPLSTYFSAVKLRWLLDNVRKVQKAVEEKRALFGTIDS
  WLIWSLTGGVNGGVHCTDVTNASRTMLFNIHSLEWDKQLCEFFGIPMEILPNVRSSSEIY
  GLMKISHSVKAGALEGVPISGCLGDQSAALVGQMCFQIGQAKNTYGTGCFLLCNTGHKCV
  FSDHGLLTTVAYKLGRDKPVYYALEGSVAIAGAVIRWLRDNLGIIKTSEEIEKLAKEVGT
  SYGCYFVPAFSGLYAPYWEPSARGIICGLTQFTNKCHIAFAALEAVCFQTREILDAMNRD
  CGIPLSHLQVDGGMTSNKILMQLQADILYIPVVKPSMPETTALGAAMAAGAAEGVGVWSL
  EPEDLSAVTMERFEPQINAEESEIRYSTWKKAVMKSMGWVTTQSPESGDPSIFCSLPLGF
  FIVSSMVMLIGARYISGIP
• Function: Kinase that plays a key role in glycerol metabolism, catalyzing its phosphorylation to produce sn-glycerol 3-phosphate. Sn-glycerol 3-phosphate is a crucial intermediate in various metabolic pathways, such as the synthesis of glycerolipids and triglycerides, glycogenesis, glycolysis and gluconeogenesis.
• Tissue Specificity: .Widely expressed in fetal and adult tissues.; [Isoform 3]: Widely expressed in fetal and adult tissues.; [Isoform 4]: The sole isoform expressed in adult liver and kidney.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
• Reactome Pathway: Triglyceride biosynthesis (R-HSA-75109)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Becker muscular dystrophy	DIS5IYHL	Definitive	Genetic Variation	[1]
Inborn glycerol kinase deficiency	DISD1PUT	Definitive	X-linked	[2]
Aland island eye disease	DISJ457D	Strong	Biomarker	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[4]
Galactokinase deficiency	DISEB0V4	Strong	Genetic Variation	[5]
Hypogonadism	DISICMNI	Strong	Biomarker	[6]
Hypogonadotropic hypogonadism	DIS8JSKR	Strong	Genetic Variation	[7]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[8]
Klinefelter syndrome	DISOUI7W	Strong	Genetic Variation	[9]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Altered Expression	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[3]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[12]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[13]
Familial hypercholesterolemia	DISC06IX	moderate	Biomarker	[14]
X-linked adrenal hypoplasia congenita	DISNMXY8	moderate	Genetic Variation	[15]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[16]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[17]

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 Glycerol kinase (GK).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glycerol kinase (GK).	[35]

18 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 Glycerol kinase (GK).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycerol kinase (GK).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glycerol kinase (GK).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glycerol kinase (GK).	[22]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Glycerol kinase (GK).	[23]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Glycerol kinase (GK).	[24]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Glycerol kinase (GK).	[25]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glycerol kinase (GK).	[26]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glycerol kinase (GK).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Glycerol kinase (GK).	[28]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Glycerol kinase (GK).	[29]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Glycerol kinase (GK).	[30]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Glycerol kinase (GK).	[31]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Glycerol kinase (GK).	[32]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Glycerol kinase (GK).	[33]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycerol kinase (GK).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycerol kinase (GK).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Glycerol kinase (GK).	[37]

References

• [1] A point mutation in the glycerol kinase gene associated with a deletion in the dystrophin gene in a familial X-linked muscular dystrophy: non-contiguous gene syndrome involving Becker muscular dystrophy and glycerol kinase loci.Neuromuscul Disord. 1997 Dec;7(8):499-504. doi: 10.1016/s0960-8966(97)00114-4.
• [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] Mental retardation locus in Xp21 chromosome microdeletion.Am J Med Genet. 1993 Jun 1;46(4):363-8. doi: 10.1002/ajmg.1320460404.
• [4] Novel mutations and spectrum of the disease of NR0B1 (DAX1)-related adrenal insufficiency in Indian children.J Pediatr Endocrinol Metab. 2019 Aug 27;32(8):863-869. doi: 10.1515/jpem-2018-0440.
• [5] A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am J Hum Genet. 1999 Nov;65(5):1299-307. doi: 10.1086/302611.
• [6] Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.Am J Med Genet. 1988 Nov;31(3):603-16. doi: 10.1002/ajmg.1320310315.
• [7] Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency.Eur J Pediatr. 1992 Mar;151(3):167-9. doi: 10.1007/BF01954375.
• [8] Characterization of the human glycerol kinase promoter: identification of a functional HNF-4alpha binding site and evidence for transcriptional activation.Mol Genet Metab. 2003 Dec;80(4):412-8. doi: 10.1016/j.ymgme.2003.10.003.
• [9] Molecular Xp deletion in a male: suggestion of a locus for hypogonadotropic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci.Clin Genet. 1989 Jan;35(1):5-12. doi: 10.1111/j.1399-0004.1989.tb02899.x.
• [10] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [11] Implications of Aquaglyceroporin 7 in Energy Metabolism.Int J Mol Sci. 2018 Jan 4;19(1):154. doi: 10.3390/ijms19010154.
• [12] Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy.mBio. 2019 Jul 30;10(4):e00663-19. doi: 10.1128/mBio.00663-19.
• [13] Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver.FASEB J. 2019 Jun;33(6):6736-6747. doi: 10.1096/fj.201800945RR. Epub 2019 Mar 1.
• [14] Lipid and glucose utilization in hypercholesterolemic rats fed a diet containing heated chickpea (Cicer aretinum L.): a potential functional food.Int J Vitam Nutr Res. 1999 Nov;69(6):403-11. doi: 10.1024/0300-9831.69.6.403.
• [15] A case of X-linked adrenal hypoplasia congenita, central precocious puberty and absence of the DAX-1 gene: implications for pubertal regulation.Horm Res. 2009;71(5):298-304. doi: 10.1159/000208804. Epub 2009 Apr 1.
• [16] Mutations and phenotype in isolated glycerol kinase deficiency.Am J Hum Genet. 1996 Jun;58(6):1205-11.
• [17] Transcriptomic and network component analysis of glycerol kinase in skeletal muscle using a mouse model of glycerol kinase deficiency.Mol Genet Metab. 2009 Mar;96(3):106-12. doi: 10.1016/j.ymgme.2008.11.163. Epub 2009 Jan 3.
• [18] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [19] 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.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [24] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [25] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [26] 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.
• [27] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [28] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [29] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [30] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [31] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [32] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [33] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] 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.
• [36] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [37] 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.