Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0T02Q)

• DOT Name: Adenylate kinase 4, mitochondrial (AK4)
• Synonyms: AK 4; EC 2.7.4.10; EC 2.7.4.6; Adenylate kinase 3-like; GTP:AMP phosphotransferase AK4
• Gene Name: AK4
• Related Disease:
  Actinic keratosis
  Advanced cancer
  Breast cancer
  Breast carcinoma
  HER2/NEU overexpressing breast cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Short chain acyl-CoA dehydrogenase deficiency
  Venous thromboembolism
  Amyotrophic lateral sclerosis
  Bladder cancer
  Osteoarthritis
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: KAD4_HUMAN
• PDB ID: 2AR7; 2BBW; 3NDP
• EC Number: 2.7.4.10; 2.7.4.6
• Pfam ID: PF00406 ; PF05191
• Sequence:
  MASKLLRAVILGPPGSGKGTVCQRIAQNFGLQHLSSGHFLRENIKASTEVGEMAKQYIEK
  SLLVPDHVITRLMMSELENRRGQHWLLDGFPRTLGQAEALDKICEVDLVISLNIPFETLK
  DRLSRRWIHPPSGRVYNLDFNPPHVHGIDDVTGEPLVQQEDDKPEAVAARLRQYKDVAKP
  VIELYKSRGVLHQFSGTETNKIWPYVYTLFSNKITPIQSKEAY
• Function: Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Efficiently phosphorylates AMP and dAMP using ATP as phosphate donor, but phosphorylates only AMP when using GTP as phosphate donor. Also displays broad nucleoside diphosphate kinase activity. Plays a role in controlling cellular ATP levels by regulating phosphorylation and activation of the energy sensor protein kinase AMPK. Plays a protective role in the cellular response to oxidative stress.
• Tissue Specificity: Highly expressed in kidney, moderately expressed in heart and liver and weakly expressed in brain.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Actinic keratosis	DISR1RC5	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Short chain acyl-CoA dehydrogenase deficiency	DISDDRPY	Strong	Biomarker	[4]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[6]
Bladder cancer	DISUHNM0	Limited	Biomarker	[7]
Osteoarthritis	DIS05URM	Limited	Biomarker	[8]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[7]

1 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 Adenylate kinase 4, mitochondrial (AK4).	[9]

29 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 Adenylate kinase 4, mitochondrial (AK4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Adenylate kinase 4, mitochondrial (AK4).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[21]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Adenylate kinase 4, mitochondrial (AK4).	[22]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[15]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[15]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[15]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[23]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[26]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adenylate kinase 4, mitochondrial (AK4).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adenylate kinase 4, mitochondrial (AK4).	[33]

References

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• [22] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
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