Details of Drug Off-Target (DOT)

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

• DOT Name: AP-5 complex subunit zeta-1 (AP5Z1)
• Synonyms: Adaptor-related protein complex 5 zeta subunit; Zeta5
• Gene Name: AP5Z1
• Related Disease:
  Hereditary spastic paraplegia
  Alpha thalassemia
  Astrocytoma
  Beta thalassemia
  Carcinoma
  Hematologic disease
  Hemoglobin H disease
  Hereditary spastic paraplegia 48
  Metastatic malignant neoplasm
  Neoplasm
  Systemic lupus erythematosus
• UniProt ID: AP5Z1_HUMAN
• Pfam ID: PF14764
• Sequence:
  MFSAGAESLLHQAREIQDEELKKFCSRICKLLQAEDLGPDTLDSLQRLFLIISATKYSRR
  LEKTCVDLLQATLGLPACPEQLQVLCAAILREMSPSDSLSLAWDHTQNSRQLSLVASVLL
  AQGDRNEEVRAVGQGVLRALESRQPEGPSLRHLLPVMAKVVVLSPGTLQEDQATLLSKRL
  VDWLRYASLQQGLPHSGGFFSTPRARQPGPVTEVDGAVATDFFTVLSSGHRFTDDQWLNV
  QAFSMLRAWLLHSGPEGPGTLDTDDRSEQEGSTLSVISATSSAGRLLPPRERLREVAFEY
  CQRLIEQSNRRALRKGDSDLQKACLVEAVLVLDVLCRQDPSFLYRSLSCLKALHGRVRGD
  PASVRVLLPLAHFFLSHGEAAAVDSEAVYQHLFTRIPVEQFHSPMLAFEFIQFCRDNLHL
  FSGHLSTLRLSFPNLFKFLAWNSPPLTSEFVALLPALVDAGTALEMLHALLDLPCLTAVL
  DLQLRSAPAASERPLWDTSLRAPSCLEAFRDPQFQGLFQYLLRPKASGATERLAPLHQLL
  QPMAGCARVAQCAQAVPTLLQAFFSAVTQVADGSLINQLALLLLGRSDSLYPAPGYAAGV
  HSVLSSQFLALCTLKPSLVVELARDLLEFLGSVNGLCSRASLVTSVVWAIGEYLSVTYDR
  RCTVEQINKFFEALEALLFEVTQCRPSAALPRCPPQVVTVLMTTLTKLASRSQDLIPRAS
  LLLSKMRTLAHSPATSSTHSEEGAEAIRTRATELLTLLKMPSVAQFVLTPSTEVCSPRYH
  RDANTALPLALRTVSRLVEREAGLMPG
• Function: As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862 it is a putative helicase required for efficient homologous recombination DNA double-strand break repair.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary spastic paraplegia	DISGZQV1	Definitive	Autosomal recessive	[1]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[6]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[7]
Hereditary spastic paraplegia 48	DIS7MLM9	Strong	Autosomal recessive	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of AP-5 complex subunit zeta-1 (AP5Z1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[19]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of AP-5 complex subunit zeta-1 (AP5Z1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of AP-5 complex subunit zeta-1 (AP5Z1).	[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] Alpha-thalassaemia and globin gene rearrangements in French Polynesia.Eur J Haematol. 1995 Sep;55(3):171-7. doi: 10.1111/j.1600-0609.1995.tb00246.x.
• [3] Gene expression analyses of grade II gliomas and identification of rPTPbeta/zeta as a candidate oligodendroglioma marker.Neuro Oncol. 2008 Feb;10(1):2-9. doi: 10.1215/15228517-2007-041. Epub 2007 Nov 14.
• [4] The risk of alpha-thalassaemia in offspring of beta-thalassaemia carriers in Hong Kong.Prenat Diagn. 1997 Aug;17(8):733-6.
• [5] Expression of the opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor in head and neck squamous cell carcinoma.Laryngoscope. 1997 Mar;107(3):335-9. doi: 10.1097/00005537-199703000-00011.
• [6] Alterations in the expression pattern of TCR zeta chain in T cells from patients with hematological diseases.Hematology. 2008 Oct;13(5):267-75. doi: 10.1179/102453308X343482.
• [7] A new gene deletion in the alpha-like globin gene cluster as the molecular basis for the rare alpha-thalassemia-1(--/alpha alpha) in blacks: HbH disease in sickle cell trait.Blood. 1986 Feb;67(2):469-73.
• [8] A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010 Jun 29;8(6):e1000408. doi: 10.1371/journal.pbio.1000408.
• [9] Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors.Blood. 2002 Nov 1;100(9):3155-63. doi: 10.1182/blood-2002-04-1041.
• [10] Stability and translation of TCR zeta mRNA are regulated by the adenosine-uridine-rich elements in splice-deleted 3' untranslated region of zeta-chain.J Immunol. 2006 Dec 1;177(11):8248-57. doi: 10.4049/jimmunol.177.11.8248.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [19] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.