Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPFQ2QC)

• DOT Name: Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1)
• Synonyms: Centaurin-beta-1; Cnt-b1
• Gene Name: ACAP1
• Related Disease:
  Alzheimer disease
  Hypothyroidism
• UniProt ID: ACAP1_HUMAN
• PDB ID: 3JUE; 3T9K; 4CKG; 4CKH; 4F1P; 4NSW; 5H3D
• Pfam ID: PF12796 ; PF01412 ; PF16746 ; PF00169
• Sequence:
  MTVKLDFEECLKDSPRFRASIELVEAEVSELETRLEKLLKLGTGLLESGRHYLAASRAFV
  VGICDLARLGPPEPMMAECLEKFTVSLNHKLDSHAELLDATQHTLQQQIQTLVKEGLRGF
  REARRDFWRGAESLEAALTHNAEVPRRRAQEAEEAGAALRTARAGYRGRALDYALQINVI
  EDKRKFDIMEFVLRLVEAQATHFQQGHEELSRLSQYRKELGAQLHQLVLNSAREKRDMEQ
  RHVLLKQKELGGEEPEPSLREGPGGLVMEGHLFKRASNAFKTWSRRWFTIQSNQLVYQKK
  YKDPVTVVVDDLRLCTVKLCPDSERRFCFEVVSTSKSCLLQADSERLLQLWVSAVQSSIA
  SAFSQARLDDSPRGPGQGSGHLAIGSAATLGSGGMARGREPGGVGHVVAQVQSVDGNAQC
  CDCREPAPEWASINLGVTLCIQCSGIHRSLGVHFSKVRSLTLDSWEPELVKLMCELGNVI
  INQIYEARVEAMAVKKPGPSCSRQEKEAWIHAKYVEKKFLTKLPEIRGRRGGRGRPRGQP
  PVPPKPSIRPRPGSLRSKPEPPSEDLGSLHPGALLFRASGHPPSLPTMADALAHGADVNW
  VNGGQDNATPLIQATAANSLLACEFLLQNGANVNQADSAGRGPLHHATILGHTGLACLFL
  KRGADLGARDSEGRDPLTIAMETANADIVTLLRLAKMREAEAAQGQAGDETYLDIFRDFS
  LMASDDPEKLSRRSHDLHTL
• Function: GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6) required for clathrin-dependent export of proteins from recycling endosomes to trans-Golgi network and cell surface. Required for regulated export of ITGB1 from recycling endosomes to the cell surface and ITGB1-dependent cell migration.
• Tissue Specificity: Highest level in lung and spleen. Low level in heart, kidney, liver and pancreas.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[4]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 (ACAP1).	[9]

References

• [1] Translational study of Alzheimer's disease (AD) biomarkers from brain tissues in APP/PS1 mice and serum of AD patients.J Alzheimers Dis. 2015;45(1):269-82. doi: 10.3233/JAD-142805.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [6] 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.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [8] 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.
• [9] 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.