Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUH9JPD)

• DOT Name: Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1)
• Synonyms: Adapter protein X11alpha; Neuron-specific X11 protein; Neuronal Munc18-1-interacting protein 1; Mint-1
• Gene Name: APBA1
• Related Disease:
  Adenocarcinoma
  Adenoma
  Alzheimer disease
  Carcinoma
  Colorectal carcinoma
  Cytomegalovirus infection
  Familial adenomatous polyposis
  Hereditary nonpolyposis colon cancer
  Neoplasm
  Schizophrenia
  Stomach cancer
  Ulcerative colitis
  Gastrointestinal stromal tumour
  Kaposi sarcoma
• UniProt ID: APBA1_HUMAN
• PDB ID: 1AQC; 1U37; 1U38; 1U39; 1U3B; 1X11; 1X45; 1Y7N
• Pfam ID: PF00595 ; PF00640
• Sequence:
  MNHLEGSAEVEVTDEAAGGEVNESVEADLEHPEVEEEQQQPPQQQHYVGRHQRGRALEDL
  RAQLGQEEEERGECLARSASTESGFHNHTDTAEGDVIAAARDGYDAERAQDPEDESAYAV
  QYRPEAEEYTEQAEAEHAEATHRRALPNHLHFHSLEHEEAMNAAYSGYVYTHRLFHRGED
  EPYSEPYADYGGLQEHVYEEIGDAPELDARDGLRLYEQERDEAAAYRQEALGARLHHYDE
  RSDGESDSPEKEAEFAPYPRMDSYEQEEDIDQIVAEVKQSMSSQSLDKAAEDMPEAEQDL
  ERPPTPAGGRPDSPGLQAPAGQQRAVGPAGGGEAGQRYSKEKRDAISLAIKDIKEAIEEV
  KTRTIRSPYTPDEPKEPIWVMRQDISPTRDCDDQRPMDGDSPSPGSSSPLGAESSSTSLH
  PSDPVEASTNKESRKSLASFPTYVEVPGPCDPEDLIDGIIFAANYLGSTQLLSDKTPSKN
  VRMMQAQEAVSRIKMAQKLAKSRKKAPEGESQPMTEVDLFISTQRIKVLNADTQETMMDH
  PLRTISYIADIGNIVVLMARRRMPRSNSQENVEASHPSQDGKRQYKMICHVFESEDAQLI
  AQSIGQAFSVAYQEFLRANGINPEDLSQKEYSDLLNTQDMYNDDLIHFSKSENCKDVFIE
  KQKGEILGVVIVESGWGSILPTVIIANMMHGGPAEKSGKLNIGDQIMSINGTSLVGLPLS
  TCQSIIKGLKNQSRVKLNIVRCPPVTTVLIRRPDLRYQLGFSVQNGIICSLMRGGIAERG
  GVRVGHRIIEINGQSVVATPHEKIVHILSNAVGEIHMKTMPAAMYRLLTAQEQPVYI
• Function: Putative function in synaptic vesicle exocytosis by binding to Munc18-1, an essential component of the synaptic vesicle exocytotic machinery. May modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules.
• Tissue Specificity: Brain and spinal cord. Isoform 2 is expressed in testis and brain, but not detected in lung, liver or spleen.
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Posttranslational Modification	[1]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[5]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[7]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[12]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Posttranslational Modification	[13]
Kaposi sarcoma	DISC1H1Z	Disputed	Genetic Variation	[5]

2 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 Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1).	[22]

References

• [1] Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas.Oncogene. 2004 Jun 3;23(26):4646-54. doi: 10.1038/sj.onc.1207588.
• [2] Case-control study of candidate gene methylation and adenomatous polyp formation.Int J Colorectal Dis. 2017 Feb;32(2):183-192. doi: 10.1007/s00384-016-2688-1. Epub 2016 Oct 22.
• [3] Expression of the neuronal adaptor protein X11alpha protects against memory dysfunction in a transgenic mouse model of Alzheimer's disease.J Alzheimers Dis. 2010;20(1):31-6. doi: 10.3233/JAD-2009-1341.
• [4] Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas.Gastroenterology. 2003 May;124(5):1300-10. doi: 10.1016/s0016-5085(03)00278-6.
• [5] Detection of viral DNA sequences in sporadic colorectal cancers in relation to CpG island methylation and methylator phenotype.Tumour Biol. 2011 Aug;32(4):653-9. doi: 10.1007/s13277-011-0165-6. Epub 2011 Apr 6.
• [6] NSF, Unc-18-1, dynamin-1 and HSP90 are inclusion body components in neuronal intranuclear inclusion disease identified by anti-SUMO-1-immunocapture.Acta Neuropathol. 2008 Dec;116(6):603-14. doi: 10.1007/s00401-008-0437-4. Epub 2008 Oct 3.
• [7] Hypermethylation status of APC inversely correlates with the presence of submucosal invasion in laterally spreading colorectal tumors.Mol Carcinog. 2008 Jan;47(1):1-8. doi: 10.1002/mc.20363.
• [8] Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer.Fam Cancer. 2004;3(2):101-7. doi: 10.1023/B:FAME.0000039861.30651.c8.
• [9] Concordant DNA methylation in synchronous colorectal carcinomas.Cancer Prev Res (Phila). 2009 Sep;2(9):814-22. doi: 10.1158/1940-6207.CAPR-09-0054. Epub 2009 Sep 8.
• [10] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [11] Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma.Am J Pathol. 2002 Mar;160(3):787-94. doi: 10.1016/S0002-9440(10)64901-2.
• [12] Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer.Am J Gastroenterol. 2010 Jul;105(7):1610-9. doi: 10.1038/ajg.2010.22. Epub 2010 Feb 16.
• [13] Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy.Cancer Sci. 2008 Feb;99(2):253-9. doi: 10.1111/j.1349-7006.2007.00682.x.
• [14] 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.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.