Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZG3X2H)

• DOT Name: Adenylate kinase 2, mitochondrial (AK2)
• Synonyms: AK 2; EC 2.7.4.3; ATP-AMP transphosphorylase 2; ATP:AMP phosphotransferase; Adenylate monophosphate kinase
• Gene Name: AK2
• Related Disease: Reticular dysgenesis
• UniProt ID: KAD2_HUMAN
• PDB ID: 2C9Y
• EC Number: 2.7.4.3
• Pfam ID: PF00406 ; PF05191
• Sequence:
  MAPSVPAAEPEYPKGIRAVLLGPPGAGKGTQAPRLAENFCVCHLATGDMLRAMVASGSEL
  GKKLKATMDAGKLVSDEMVVELIEKNLETPLCKNGFLLDGFPRTVRQAEMLDDLMEKRKE
  KLDSVIEFSIPDSLLIRRITGRLIHPKSGRSYHEEFNPPKEPMKDDITGEPLIRRSDDNE
  KALKIRLQAYHTQTTPLIEYYRKRGIHSAIDASQTPDVVFASILAAFSKATCKDLVMFI
• Function: Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis.
• Tissue Specificity: Present in most tissues. Present at high level in heart, liver and kidney, and at low level in brain, skeletal muscle and skin. Present in thrombocytes but not in erythrocytes, which lack mitochondria. Present in all nucleated cell populations from blood, while AK1 is mostly absent. In spleen and lymph nodes, mononuclear cells lack AK1, whereas AK2 is readily detectable. These results indicate that leukocytes may be susceptible to defects caused by the lack of AK2, as they do not express AK1 in sufficient amounts to compensate for the AK2 functional deficits (at protein level).
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Reticular dysgenesis	DISO6W6V	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Adenylate kinase 2, mitochondrial (AK2) increases the response to substance of Irinotecan.	[19]
Afimoxifene	DMFORDT	Phase 2	Adenylate kinase 2, mitochondrial (AK2) decreases the response to substance of Afimoxifene.	[20]

17 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 2, mitochondrial (AK2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Adenylate kinase 2, mitochondrial (AK2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Adenylate kinase 2, mitochondrial (AK2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Adenylate kinase 2, mitochondrial (AK2).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Adenylate kinase 2, mitochondrial (AK2).	[9]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Adenylate kinase 2, mitochondrial (AK2).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adenylate kinase 2, mitochondrial (AK2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Adenylate kinase 2, mitochondrial (AK2).	[17]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Adenylate kinase 2, mitochondrial (AK2).	[18]

1 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 decreases the methylation of Adenylate kinase 2, mitochondrial (AK2).	[12]

References

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• [8] 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.
• [9] 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.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] 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.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] 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.
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• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [18] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [19] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [20] 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.