Details of Drug Off-Target (DOT)

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

• DOT Name: Copper-transporting ATPase 2 (ATP7B)
• Synonyms: EC 7.2.2.8; Copper pump 2; Wilson disease-associated protein
• Gene Name: ATP7B
• Related Disease: Wilson disease
• UniProt ID: ATP7B_HUMAN
• PDB ID: 2ARF; 2EW9; 2KOY; 2LQB; 2N7Y; 2ROP; 6A71; 6A72; 7XUK; 7XUM; 7XUN; 7XUO; 8IOY
• EC Number: 7.2.2.8
• Pfam ID: PF00122 ; PF00403 ; PF00702
• Sequence:
  MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS
  TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG
  FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN
  QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN
  QNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVK
  YDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCST
  TLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDM
  GFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQ
  STRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPL
  EIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALA
  TSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWKKSFLCSLVF
  GIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGGWYFYVQAYK
  SLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLFVFIALGRWL
  EHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIVKVVPGGKFP
  VDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVGNDTTLAQIV
  KLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQRYFPNPNKH
  ISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGGKPLEMAHK
  IKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPLGVAVTKYCK
  EELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAGSLPAEKDAV
  PQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQ
  EAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAKVQELQNKGK
  KVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASIHLSKRTVRR
  IRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPD
  LERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSR
  HSAAADDDGDKWSLLLNGRDEEQYI
• Function: Copper ion transmembrane transporter involved in the export of copper out of the cells. It is involved in copper homeostasis in the liver, where it ensures the efflux of copper from hepatocytes into the bile in response to copper overload.
• Tissue Specificity: Most abundant in liver and kidney and also found in brain. Isoform 2 is expressed in brain but not in liver. The cleaved form WND/140 kDa is found in liver cell lines and other tissues.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Mineral absorption (hsa04978)
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Wilson disease	DISVS9H7	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Copper-transporting ATPase 2 (ATP7B) decreases the response to substance of Cisplatin.	[22]
Fluorouracil	DMUM7HZ	Approved	Copper-transporting ATPase 2 (ATP7B) increases the response to substance of Fluorouracil.	[23]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Copper-transporting ATPase 2 (ATP7B) decreases the abundance of Glutathione.	[24]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Protoporphyrin IX	DMWYE7A	Investigative	Copper-transporting ATPase 2 (ATP7B) decreases the chemical synthesis of Protoporphyrin IX.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Copper-transporting ATPase 2 (ATP7B).	[2]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the phosphorylation of Copper-transporting ATPase 2 (ATP7B).	[14]
Magnesium	DMU4ORS	Approved	Magnesium increases the phosphorylation of Copper-transporting ATPase 2 (ATP7B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Copper-transporting ATPase 2 (ATP7B).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Copper-transporting ATPase 2 (ATP7B).	[18]
Manganese	DMKT129	Investigative	Manganese increases the phosphorylation of Copper-transporting ATPase 2 (ATP7B).	[14]
CID755673	DMSHIQA	Investigative	CID755673 decreases the phosphorylation of Copper-transporting ATPase 2 (ATP7B).	[17]

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 Copper-transporting ATPase 2 (ATP7B).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Copper-transporting ATPase 2 (ATP7B).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Copper-transporting ATPase 2 (ATP7B).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Copper-transporting ATPase 2 (ATP7B).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[13]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Copper-transporting ATPase 2 (ATP7B).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Copper-transporting ATPase 2 (ATP7B).	[20]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Copper-transporting ATPase 2 (ATP7B).	[21]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Copper-transporting ATPase 2 (ATP7B).	[17]

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] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] The loop connecting metal-binding domains 3 and 4 of ATP7B is a target of a kinase-mediated phosphorylation. Biochemistry. 2009 Jun 23;48(24):5573-81. doi: 10.1021/bi900325k.
• [15] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [16] 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.
• [17] Involvement of protein kinase D in expression and trafficking of ATP7B (copper ATPase). J Biol Chem. 2011 Mar 4;286(9):7389-96. doi: 10.1074/jbc.M110.171454. Epub 2010 Dec 27.
• [18] 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.
• [19] 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.
• [20] Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 2014 Oct 15;74(20):5819-31. doi: 10.1158/0008-5472.CAN-13-3527.
• [21] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [22] Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res. 2000 Mar 1;60(5):1312-6.
• [23] Single-cell transcription site activation predicts chemotherapy response in human colorectal tumors. Cancer Res. 2008 Jul 1;68(13):4977-82. doi: 10.1158/0008-5472.CAN-07-6770.
• [24] Treatment with D-penicillamine or zinc sulphate affects copper metabolism and improves but not normalizes antioxidant capacity parameters in Wilson disease. Biometals. 2014 Feb;27(1):207-15. doi: 10.1007/s10534-013-9694-3. Epub 2013 Dec 25.
• [25] Regulation of heme synthesis and proteasomal activity by copper: possible implications for Wilson's disease. J Environ Pathol Toxicol Oncol. 2009;28(3):209-21.