Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT614AR3)

• DOT Name: Adenylate kinase isoenzyme 1 (AK1)
• Synonyms: AK 1; EC 2.7.4.10; EC 2.7.4.3; EC 2.7.4.6; ATP-AMP transphosphorylase 1; ATP:AMP phosphotransferase; Adenylate monophosphate kinase; Myokinase
• Gene Name: AK1
• Related Disease:
  Hemolytic anemia due to adenylate kinase deficiency
  Lung adenocarcinoma
  Myocardial ischemia
  Nail-patella syndrome
  Non-insulin dependent diabetes
  Schizophrenia
  Myocardial infarction
• UniProt ID: KAD1_HUMAN
• PDB ID: 1Z83; 2C95; 7DE3; 7X7S
• EC Number: 2.7.4.10; 2.7.4.3; 2.7.4.6
• Pfam ID: PF00406
• Sequence:
  MEEKLKKTKIIFVVGGPGSGKGTQCEKIVQKYGYTHLSTGDLLRSEVSSGSARGKKLSEI
  MEKGQLVPLETVLDMLRDAMVAKVNTSKGFLIDGYPREVQQGEEFERRIGQPTLLLYVDA
  GPETMTQRLLKRGETSGRVDDNEETIKKRLETYYKATEPVIAFYEKRGIVRKVNAEGSVD
  SVFSQVCTHLDALK
• Function: Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Exhibits nucleoside diphosphate kinase activity, catalyzing the production of ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and dTTP from the corresponding diphosphate substrates with either ATP or GTP as phosphate donor. Also catalyzes at a very low rate the synthesis of thiamine triphosphate (ThTP) from thiamine diphosphate (ThDP) and ADP.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Thiamine metabolism (hsa00730)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Interconversion of nucleotide di- and triphosphates (R-HSA-499943)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemolytic anemia due to adenylate kinase deficiency	DIS6A0ZV	Strong	Autosomal recessive	[1]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[2]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[3]
Nail-patella syndrome	DIS8C4CT	Strong	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[6]
Myocardial infarction	DIS655KI	Limited	Therapeutic	[7]

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aminoglutethimide	DMWFHMZ	Approved	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of Aminoglutethimide.	[20]
Exemestane	DM9HPW3	Approved	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of Exemestane.	[20]
Letrozole	DMH07Y3	Approved	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of Letrozole.	[20]
Anastrozole	DMNP60F	Approved	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of Anastrozole.	[20]
FORMESTANE	DMWIDJK	Withdrawn from market	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of FORMESTANE.	[20]
VOROZOLE	DM32N5G	Discontinued in Phase 2	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of VOROZOLE.	[20]
Rogletimide	DM6JO30	Terminated	Adenylate kinase isoenzyme 1 (AK1) increases the Cardiovascular disorder ADR of Rogletimide.	[20]

14 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 Adenylate kinase isoenzyme 1 (AK1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Adenylate kinase isoenzyme 1 (AK1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenylate kinase isoenzyme 1 (AK1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Adenylate kinase isoenzyme 1 (AK1).	[14]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[15]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the activity of Adenylate kinase isoenzyme 1 (AK1).	[16]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Adenylate kinase isoenzyme 1 (AK1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Adenylate kinase isoenzyme 1 (AK1).	[18]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Adenylate kinase isoenzyme 1 (AK1).	[19]

References

• [1] A case of complete adenylate kinase deficiency due to a nonsense mutation in AK-1 gene (Arg 107 --> Stop, CGA --> TGA) associated with chronic haemolytic anaemia. Br J Haematol. 1999 Apr;105(1):75-9.
• [2] A co-expressed gene status of adenylate kinase 1/4 reveals prognostic gene signature associated with prognosis and sensitivity to EGFR targeted therapy in lung adenocarcinoma.Sci Rep. 2019 Aug 23;9(1):12329. doi: 10.1038/s41598-019-48243-9.
• [3] 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.
• [4] Linkage analysis in two large Italian pedigrees affected with nail patella syndrome.Eur J Hum Genet. 1998 Jul-Aug;6(4):345-9. doi: 10.1038/sj.ejhg.5200191.
• [5] Proteomic profiling of non-obese type 2 diabetic skeletal muscle.Int J Mol Med. 2010 Mar;25(3):445-58. doi: 10.3892/ijmm_00000364.
• [6] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [7] Resveratrol protects left ventricle by increasing adenylate kinase and isocitrate dehydrogenase activities in rats with myocardial infarction.Chin J Physiol. 2011 Dec 31;54(6):406-12. doi: 10.4077/CJP.2011.AMM097.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes. Drug Metabol Drug Interact. 2008;23(3-4):211-36.
• [17] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [18] 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.
• [19] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [20] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.