Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM59ZGG)

• DOT Name: GTP:AMP phosphotransferase AK3, mitochondrial (AK3)
• Synonyms: EC 2.7.4.10; Adenylate kinase 3; AK 3; Adenylate kinase 3 alpha-like 1
• Gene Name: AK3
• Related Disease:
  Arthropathy
  Actinic keratosis
  Advanced cancer
  Anemia
  Bleeding disorder
  Cardiac failure
  Coagulation defect
  Congestive heart failure
  Severe hemophilia A
  Small lymphocytic lymphoma
  Von willebrand disease
  Mild hemophilia A
  Type-1/2 diabetes
  Migraine disorder
• UniProt ID: KAD3_HUMAN
• PDB ID: 1ZD8; 6ZJB; 6ZJD; 6ZJE
• EC Number: 2.7.4.10
• Pfam ID: PF00406 ; PF05191
• Sequence:
  MGASARLLRAVIMGAPGSGKGTVSSRITTHFELKHLSSGDLLRDNMLRGTEIGVLAKAFI
  DQGKLIPDDVMTRLALHELKNLTQYSWLLDGFPRTLPQAEALDRAYQIDTVINLNVPFEV
  IKQRLTARWIHPASGRVYNIEFNPPKTVGIDDLTGEPLIQREDDKPETVIKRLKAYEDQT
  KPVLEYYQKKGVLETFSGTETNKIWPYVYAFLQTKVPQRSQKASVTP
• Function: Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Has GTP:AMP phosphotransferase and ITP:AMP phosphotransferase activities.
• Tissue Specificity: Highly expressed in heart, skeletal muscle and liver, moderately expressed in pancreas and kidney, and weakly expressed in placenta, brain and lung.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthropathy	DISVEERK	Definitive	Biomarker	[1]
Actinic keratosis	DISR1RC5	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Anemia	DISTVL0C	Strong	Biomarker	[4]
Bleeding disorder	DIS27CUA	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Genetic Variation	[6]
Coagulation defect	DIS9X3H6	Strong	Altered Expression	[7]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[6]
Severe hemophilia A	DISXUFDW	Strong	Biomarker	[1]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[8]
Von willebrand disease	DIS3TZCH	Strong	Biomarker	[9]
Mild hemophilia A	DISFYEEB	moderate	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Disputed	Altered Expression	[11]
Migraine disorder	DISFCQTG	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[21]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[17]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[26]

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 GTP:AMP phosphotransferase AK3, mitochondrial (AK3).	[22]

References

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• [10] Can we compare haemophilia carriers with clotting factor deficiency to male patients with mild haemophilia?.Haemophilia. 2020 Jan;26(1):117-121. doi: 10.1111/hae.13891. Epub 2019 Dec 9.
• [11] Glucose metabolism affects coagulation factors: The NEO study.J Thromb Haemost. 2019 Nov;17(11):1886-1897. doi: 10.1111/jth.14573. Epub 2019 Aug 9.
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• [18] 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.
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• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.