Details of Drug Off-Target (DOT)

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

• DOT Name: Adenylate kinase isoenzyme 5 (AK5)
• Synonyms: AK 5; EC 2.7.4.3; EC 2.7.4.6; ATP-AMP transphosphorylase 5
• Gene Name: AK5
• Related Disease:
  Narcolepsy
  Multiple sclerosis
  Lung adenocarcinoma
  Lung carcinoma
• UniProt ID: KAD5_HUMAN
• PDB ID: 2BWJ
• EC Number: 2.7.4.3; 2.7.4.6
• Pfam ID: PF00406
• Sequence:
  MNTNDAKEYLARREIPQLFESLLNGLMCSKPEDPVEYLESCLQKVKELGGCDKVKWDTFV
  SQEKKTLPPLNGGQSRRSFLRNVMPENSNFPYRRYDRLPPIHQFSIESDTDLSETAELIE
  EYEVFDPTRPRPKIILVIGGPGSGKGTQSLKIAERYGFQYISVGELLRKKIHSTSSNRKW
  SLIAKIITTGELAPQETTITEIKQKLMQIPDEEGIVIDGFPRDVAQALSFEDQICTPDLV
  VFLACANQRLKERLLKRAEQQGRPDDNVKATQRRLMNFKQNAAPLVKYFQEKGLIMTFDA
  DRDEDEVFYDISMAVDNKLFPNKEAAAGSSDLDPSMILDTGEIIDTGSDYEDQGDDQLNV
  FGEDTMGGFMEDLRKCKIIFIIGGPGSGKGTQCEKLVEKYGFTHLSTGELLREELASESE
  RSKLIRDIMERGDLVPSGIVLELLKEAMVASLGDTRGFLIDGYPREVKQGEEFGRRIGDP
  QLVICMDCSADTMTNRLLQRSRSSLPVDDTTKTIAKRLEAYYRASIPVIAYYETKTQLHK
  INAEGTPEDVFLQLCTAIDSIF
• Function: Nucleoside monophosphate (NMP) kinase that catalyzes the reversible transfer of the terminal phosphate group between nucleoside triphosphates and monophosphates. Active on AMP and dAMP with ATP as a donor. When GTP is used as phosphate donor, the enzyme phosphorylates AMP, CMP, and to a small extent dCMP. Also displays broad nucleoside diphosphate kinase activity.
• Tissue Specificity: Brain specific.
• 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)
• BioCyc Pathway: MetaCyc:HS07943-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[3]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Adenylate kinase isoenzyme 5 (AK5) affects the response to substance of Methamphetamine.	[17]
Afimoxifene	DMFORDT	Phase 2	Adenylate kinase isoenzyme 5 (AK5) decreases the response to substance of Afimoxifene.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Adenylate kinase isoenzyme 5 (AK5).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Adenylate kinase isoenzyme 5 (AK5).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Adenylate kinase isoenzyme 5 (AK5).	[16]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adenylate kinase isoenzyme 5 (AK5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Adenylate kinase isoenzyme 5 (AK5).	[15]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Risk alleles for multiple sclerosis identified by a genomewide study.N Engl J Med. 2007 Aug 30;357(9):851-62. doi: 10.1056/NEJMoa073493. Epub 2007 Jul 29.
• [3] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [11] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [12] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [13] 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.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.