Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51S50X)

• DOT Name: Phospholipid-transporting ATPase ABCA7 (ABCA7)
• Synonyms: EC 7.6.2.1; ABCA-SSN; ATP-binding cassette sub-family A member 7; Autoantigen SS-N; Macrophage ABC transporter
• Gene Name: ABCA7
• Related Disease: Alzheimer disease 9
• UniProt ID: ABCA7_HUMAN
• PDB ID: 8EDW; 8EE6; 8EEB; 8EOP
• EC Number: 7.6.2.1
• Pfam ID: PF12698 ; PF00005
• Sequence:
  MAFWTQLMLLLWKNFMYRRRQPVQLLVELLWPLFLFFILVAVRHSHPPLEHHECHFPNKP
  LPSAGTVPWLQGLICNVNNTCFPQLTPGEEPGRLSNFNDSLVSRLLADARTVLGGASAHR
  TLAGLGKLIATLRAARSTAQPQPTKQSPLEPPMLDVAELLTSLLRTESLGLALGQAQEPL
  HSLLEAAEDLAQELLALRSLVELRALLQRPRGTSGPLELLSEALCSVRGPSSTVGPSLNW
  YEASDLMELVGQEPESALPDSSLSPACSELIGALDSHPLSRLLWRRLKPLILGKLLFAPD
  TPFTRKLMAQVNRTFEELTLLRDVREVWEMLGPRIFTFMNDSSNVAMLQRLLQMQDEGRR
  QPRPGGRDHMEALRSFLDPGSGGYSWQDAHADVGHLVGTLGRVTECLSLDKLEAAPSEAA
  LVSRALQLLAEHRFWAGVVFLGPEDSSDPTEHPTPDLGPGHVRIKIRMDIDVVTRTNKIR
  DRFWDPGPAADPLTDLRYVWGGFVYLQDLVERAAVRVLSGANPRAGLYLQQMPYPCYVDD
  VFLRVLSRSLPLFLTLAWIYSVTLTVKAVVREKETRLRDTMRAMGLSRAVLWLGWFLSCL
  GPFLLSAALLVLVLKLGDILPYSHPGVVFLFLAAFAVATVTQSFLLSAFFSRANLAAACG
  GLAYFSLYLPYVLCVAWRDRLPAGGRVAASLLSPVAFGFGCESLALLEEQGEGAQWHNVG
  TRPTADVFSLAQVSGLLLLDAALYGLATWYLEAVCPGQYGIPEPWNFPFRRSYWCGPRPP
  KSPAPCPTPLDPKVLVEEAPPGLSPGVSVRSLEKRFPGSPQPALRGLSLDFYQGHITAFL
  GHNGAGKTTTLSILSGLFPPSGGSAFILGHDVRSSMAAIRPHLGVCPQYNVLFDMLTVDE
  HVWFYGRLKGLSAAVVGPEQDRLLQDVGLVSKQSVQTRHLSGGMQRKLSVAIAFVGGSQV
  VILDEPTAGVDPASRRGIWELLLKYREGRTLILSTHHLDEAELLGDRVAVVAGGRLCCCG
  SPLFLRRHLGSGYYLTLVKARLPLTTNEKADTDMEGSVDTRQEKKNGSQGSRVGTPQLLA
  LVQHWVPGARLVEELPHELVLVLPYTGAHDGSFATLFRELDTRLAELRLTGYGISDTSLE
  EIFLKVVEECAADTDMEDGSCGQHLCTGIAGLDVTLRLKMPPQETALENGEPAGSAPETD
  QGSGPDAVGRVQGWALTRQQLQALLLKRFLLARRSRRGLFAQIVLPALFVGLALVFSLIV
  PPFGHYPALRLSPTMYGAQVSFFSEDAPGDPGRARLLEALLQEAGLEEPPVQHSSHRFSA
  PEVPAEVAKVLASGNWTPESPSPACQCSRPGARRLLPDCPAAAGGPPPPQAVTGSGEVVQ
  NLTGRNLSDFLVKTYPRLVRQGLKTKKWVNEVRYGGFSLGGRDPGLPSGQELGRSVEELW
  ALLSPLPGGALDRVLKNLTAWAHSLDAQDSLKIWFNNKGWHSMVAFVNRASNAILRAHLP
  PGPARHAHSITTLNHPLNLTKEQLSEGALMASSVDVLVSICVVFAMSFVPASFTLVLIEE
  RVTRAKHLQLMGGLSPTLYWLGNFLWDMCNYLVPACIVVLIFLAFQQRAYVAPANLPALL
  LLLLLYGWSITPLMYPASFFFSVPSTAYVVLTCINLFIGINGSMATFVLELFSDQKLQEV
  SRILKQVFLIFPHFCLGRGLIDMVRNQAMADAFERLGDRQFQSPLRWEVVGKNLLAMVIQ
  GPLFLLFTLLLQHRSQLLPQPRVRSLPLLGEEDEDVARERERVVQGATQGDVLVLRNLTK
  VYRGQRMPAVDRLCLGIPPGECFGLLGVNGAGKTSTFRMVTGDTLASRGEAVLAGHSVAR
  EPSAAHLSMGYCPQSDAIFELLTGREHLELLARLRGVPEAQVAQTAGSGLARLGLSWYAD
  RPAGTYSGGNKRKLATALALVGDPAVVFLDEPTTGMDPSARRFLWNSLLAVVREGRSVML
  TSHSMEECEALCSRLAIMVNGRFRCLGSPQHLKGRFAAGHTLTLRVPAARSQPAAAFVAA
  EFPGAELREAHGGRLRFQLPPGGRCALARVFGELAVHGAEHGVEDFSVSQTMLEEVFLYF
  SKDQGKDEDTEEQKEAGVGVDPAPGLQHPKRVSQFLDDPSTAETVL
• Function: Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP. Transports preferentially phosphatidylserine over phosphatidylcholine. Plays a role in lipid homeostasis and macrophage-mediated phagocytosis. Binds APOA1 and may function in apolipoprotein-mediated phospholipid efflux from cells. May also mediate cholesterol efflux. May regulate cellular ceramide homeostasis during keratinocyte differentiation. Involved in lipid raft organization and CD1D localization on thymocytes and antigen-presenting cells, which plays an important role in natural killer T-cell development and activation. Plays a role in phagocytosis of apoptotic cells by macrophages. Macrophage phagocytosis is stimulated by APOA1 or APOA2, probably by stabilization of ABCA7. Also involved in phagocytic clearance of amyloid-beta by microglia cells and macrophages. Further limits amyloid-beta production by playing a role in the regulation of amyloid-beta A4 precursor protein (APP) endocytosis and/or processing. Amyloid-beta is the main component of amyloid plaques found in the brains of Alzheimer patients.
• Tissue Specificity: Expressed in leukocytes (at protein level) . Widely expressed . Highly expressed in myelo-lymphatic tissues including peripheral leukocytes, thymus, spleen and bone marrow . Expressed in the hippocampus and the cerebellum . Isoform 2: Abundant in lymph node, spleen, thymus and trachea . Isoform 1: Strongly expressed in brain and bone marrow .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway: ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease 9	DISWSNEL	Limited	Unknown	[1]

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 Phospholipid-transporting ATPase ABCA7 (ABCA7).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[16]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Phospholipid-transporting ATPase ABCA7 (ABCA7).	[17]

References

• [1] Glanzmann's thrombasthenia. Report of two oral surgical cases using a new microfibrillar collagen preparation and EACA for hemostasis. Oral Surg Oral Med Oral Pathol. 1979 Jan;47(1):36-9. doi: 10.1016/0030-4220(79)90098-7.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [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] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [15] 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.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.