Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHAO4V2)

• DOT Name: F-actin-capping protein subunit alpha-2 (CAPZA2)
• Synonyms: CapZ alpha-2
• Gene Name: CAPZA2
• Related Disease:
  Complex neurodevelopmental disorder
  Neoplasm
• UniProt ID: CAZA2_HUMAN
• Pfam ID: PF01267
• Sequence:
  MADLEEQLSDEEKVRIAAKFIIHAPPGEFNEVFNDVRLLLNNDNLLREGAAHAFAQYNLD
  QFTPVKIEGYEDQVLITEHGDLGNGKFLDPKNRICFKFDHLRKEATDPRPCEVENAVESW
  RTSVETALRAYVKEHYPNGVCTVYGKKIDGQQTIIACIESHQFQAKNFWNGRWRSEWKFT
  ITPSTTQVVGILKIQVHYYEDGNVQLVSHKDIQDSLTVSNEVQTAKEFIKIVEAAENEYQ
  TAISENYQTMSDTTFKALRRQLPVTRTKIDWNKILSYKIGKEMQNA
• Function: F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike other capping proteins (such as gelsolin and severin), these proteins do not sever actin filaments.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[1]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[8]
Aspirin	DM672AH	Approved	Aspirin increases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[9]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of F-actin-capping protein subunit alpha-2 (CAPZA2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of F-actin-capping protein subunit alpha-2 (CAPZA2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of F-actin-capping protein subunit alpha-2 (CAPZA2).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of F-actin-capping protein subunit alpha-2 (CAPZA2).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Identification of an amplified gene cluster in glioma including two novel amplified genes isolated by exon trapping.Hum Genet. 1997 Dec;101(2):190-7. doi: 10.1007/s004390050612.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [10] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.