Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMR3GXP)

• DOT Name: Copper-transporting ATPase 1 (ATP7A)
• Synonyms: EC 7.2.2.8; Copper pump 1; Menkes disease-associated protein
• Gene Name: ATP7A
• Related Disease:
  Menkes disease
  X-linked distal spinal muscular atrophy type 3
  Occipital horn syndrome
  Hirschsprung disease
• UniProt ID: ATP7A_HUMAN
• PDB ID: 1AW0; 1KVI; 1KVJ; 1Q8L; 1S6O; 1S6U; 1Y3J; 1Y3K; 1YJR; 1YJT; 1YJU; 1YJV; 2AW0; 2G9O; 2GA7; 2K1R; 2KIJ; 2KMV; 2KMX; 3CJK; 5T7L; 7LU8
• EC Number: 7.2.2.8
• Pfam ID: PF00122 ; PF00403 ; PF00702
• Sequence:
  MDPSMGVNSVTISVEGMTCNSCVWTIEQQIGKVNGVHHIKVSLEEKNATIIYDPKLQTPK
  TLQEAIDDMGFDAVIHNPDPLPVLTDTLFLTVTASLTLPWDHIQSTLLKTKGVTDIKIYP
  QKRTVAVTIIPSIVNANQIKELVPELSLDTGTLEKKSGACEDHSMAQAGEVVLKMKVEGM
  TCHSCTSTIEGKIGKLQGVQRIKVSLDNQEATIVYQPHLISVEEMKKQIEAMGFPAFVKK
  QPKYLKLGAIDVERLKNTPVKSSEGSQQRSPSYTNDSTATFIIDGMHCKSCVSNIESTLS
  ALQYVSSIVVSLENRSAIVKYNASSVTPESLRKAIEAVSPGLYRVSITSEVESTSNSPSS
  SSLQKIPLNVVSQPLTQETVINIDGMTCNSCVQSIEGVISKKPGVKSIRVSLANSNGTVE
  YDPLLTSPETLRGAIEDMGFDATLSDTNEPLVVIAQPSSEMPLLTSTNEFYTKGMTPVQD
  KEEGKNSSKCYIQVTGMTCASCVANIERNLRREEGIYSILVALMAGKAEVRYNPAVIQPP
  MIAEFIRELGFGATVIENADEGDGVLELVVRGMTCASCVHKIESSLTKHRGILYCSVALA
  TNKAHIKYDPEIIGPRDIIHTIESLGFEASLVKKDRSASHLDHKREIRQWRRSFLVSLFF
  CIPVMGLMIYMMVMDHHFATLHHNQNMSKEEMINLHSSMFLERQILPGLSVMNLLSFLLC
  VPVQFFGGWYFYIQAYKALKHKTANMDVLIVLATTIAFAYSLIILLVAMYERAKVNPITF
  FDTPPMLFVFIALGRWLEHIAKGKTSEALAKLISLQATEATIVTLDSDNILLSEEQVDVE
  LVQRGDIIKVVPGGKFPVDGRVIEGHSMVDESLITGEAMPVAKKPGSTVIAGSINQNGSL
  LICATHVGADTTLSQIVKLVEEAQTSKAPIQQFADKLSGYFVPFIVFVSIATLLVWIVIG
  FLNFEIVETYFPGYNRSISRTETIIRFAFQASITVLCIACPCSLGLATPTAVMVGTGVGA
  QNGILIKGGEPLEMAHKVKVVVFDKTGTITHGTPVVNQVKVLTESNRISHHKILAIVGTA
  ESNSEHPLGTAITKYCKQELDTETLGTCIDFQVVPGCGISCKVTNIEGLLHKNNWNIEDN
  NIKNASLVQIDASNEQSSTSSSMIIDAQISNALNAQQYKVLIGNREWMIRNGLVINNDVN
  DFMTEHERKGRTAVLVAVDDELCGLIAIADTVKPEAELAIHILKSMGLEVVLMTGDNSKT
  ARSIASQVGITKVFAEVLPSHKVAKVKQLQEEGKRVAMVGDGINDSPALAMANVGIAIGT
  GTDVAIEAADVVLIRNDLLDVVASIDLSRKTVKRIRINFVFALIYNLVGIPIAAGVFMPI
  GLVLQPWMGSAAMAASSVSVVLSSLFLKLYRKPTYESYELPARSQIGQKSPSEISVHVGI
  DDTSRNSPKLGLLDRIVNYSRASINSLLSDKRSLNSVVTSEPDKHSLLVGDFREDDDTAL
• Function: ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis. Within a catalytic cycle, acquires Cu(+) ion from donor protein on the cytoplasmic side of the membrane and delivers it to acceptor protein on the lumenal side. The transfer of Cu(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state. Under physiological conditions, at low cytosolic copper concentration, it is localized at the trans-Golgi network (TGN) where it transfers Cu(+) ions to cuproenzymes of the secretory pathway. Upon elevated cytosolic copper concentrations, it relocalizes to the plasma membrane where it is responsible for the export of excess Cu(+) ions. May play a dual role in neuron function and survival by regulating cooper efflux and neuronal transmission at the synapse as well as by supplying Cu(+) ions to enzymes such as PAM, TYR and SOD3. In the melanosomes of pigmented cells, provides copper cofactor to TYR to form an active TYR holoenzyme for melanin biosynthesis.
• Tissue Specificity: Widely expressed including in heart, brain, lung, muscle, kidney, pancreas, and to a lesser extent placenta . Expressed in fibroblasts, aortic smooth muscle cells, aortic endothelial cells and umbilical vein endothelial cells (at protein level) .; [Isoform 3]: Expressed in cerebellum and brain cortex.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Ion influx/efflux at host-pathogen interface (R-HSA-6803544)
  Ion transport by P-type ATPases (R-HSA-936837)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Menkes disease	DISJJV50	Definitive	X-linked	[1]
X-linked distal spinal muscular atrophy type 3	DIS3F79N	Definitive	X-linked	[2]
Occipital horn syndrome	DISBA58S	Strong	X-linked	[3]
Hirschsprung disease	DISUUSM1	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Copper-transporting ATPase 1 (ATP7A) decreases the response to substance of Doxorubicin.	[21]
Cisplatin	DMRHGI9	Approved	Copper-transporting ATPase 1 (ATP7A) increases the response to substance of Cisplatin.	[22]
Etoposide	DMNH3PG	Approved	Copper-transporting ATPase 1 (ATP7A) decreases the response to substance of Etoposide.	[21]
Irinotecan	DMP6SC2	Approved	Copper-transporting ATPase 1 (ATP7A) decreases the response to substance of Irinotecan.	[21]
Mitoxantrone	DMM39BF	Approved	Copper-transporting ATPase 1 (ATP7A) decreases the response to substance of Mitoxantrone.	[21]

3 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 Copper-transporting ATPase 1 (ATP7A).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Copper-transporting ATPase 1 (ATP7A).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Copper-transporting ATPase 1 (ATP7A).	[19]

13 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 Copper-transporting ATPase 1 (ATP7A).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Copper-transporting ATPase 1 (ATP7A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Copper-transporting ATPase 1 (ATP7A).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Copper-transporting ATPase 1 (ATP7A).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Copper-transporting ATPase 1 (ATP7A).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Copper-transporting ATPase 1 (ATP7A).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Copper-transporting ATPase 1 (ATP7A).	[12]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Copper-transporting ATPase 1 (ATP7A).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Copper-transporting ATPase 1 (ATP7A).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Copper-transporting ATPase 1 (ATP7A).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Copper-transporting ATPase 1 (ATP7A).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Copper-transporting ATPase 1 (ATP7A).	[18]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate decreases the expression of Copper-transporting ATPase 1 (ATP7A).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology. 2009 Jan 20;72(3):246-52. doi: 10.1212/01.wnl.0000339483.86094.a5.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet. 2020 Nov 5;16(11):e1009106. doi: 10.1371/journal.pgen.1009106. eCollection 2020 Nov.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
• [8] Effects of different sources of copper on Ctr1, ATP7A, ATP7B, MT and DMT1 protein and gene expression in Caco-2 cells. J Trace Elem Med Biol. 2014 Jul;28(3):344-50.
• [9] Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells. Biochem J. 2007 Mar 1;402(2):241-50. doi: 10.1042/BJ20061099.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Evaluation of drug transporters' significance for multidrug resistance in head and neck squamous cell carcinoma. Head Neck. 2011 Jul;33(7):959-68. doi: 10.1002/hed.21559. Epub 2010 Aug 24.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Copper egress is induced by PMA in human THP-1 monocytic cell line. Biometals. 2009 Jun;22(3):531-9. doi: 10.1007/s10534-009-9210-y. Epub 2009 Feb 10.
• [14] 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.
• [15] 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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [19] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [20] Cytotoxic effects of pyrrolidine dithiocarbamate in small-cell lung cancer cells, alone and in combination with cisplatin. Int J Oncol. 2014 Oct;45(4):1749-59. doi: 10.3892/ijo.2014.2564. Epub 2014 Jul 28.
• [21] Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer. Cancer Res. 2007 May 15;67(10):4860-8. doi: 10.1158/0008-5472.CAN-06-3096.
• [22] Copper-transporting P-type adenosine triphosphatase (ATP7A) is associated with platinum-resistance in non-small cell lung cancer (NSCLC). J Transl Med. 2012 Feb 3;10:21. doi: 10.1186/1479-5876-10-21.