Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEV2XGW)

• DOT Name: AP-2 complex subunit sigma (AP2S1)
• Synonyms: Adaptor protein complex AP-2 subunit sigma; Adaptor-related protein complex 2 subunit sigma; Clathrin assembly protein 2 sigma small chain; Clathrin coat assembly protein AP17; Clathrin coat-associated protein AP17; HA2 17 kDa subunit; Plasma membrane adaptor AP-2 17 kDa protein; Sigma2-adaptin
• Gene Name: AP2S1
• Related Disease:
  Familial hypocalciuric hypercalcemia 3
  Familial primary hyperparathyroidism
  Hyperparathyroidism
  Hypocalcemia
  Hypoparathyroidism
  Pancreatitis
  Primary hyperparathyroidism
  Autism spectrum disorder
  Hypercalcaemia
• UniProt ID: AP2S1_HUMAN
• PDB ID: 6URI
• Pfam ID: PF01217
• Sequence:
  MIRFILIQNRAGKTRLAKWYMQFDDDEKQKLIEEVHAVVTVRDAKHTNFVEFRNFKIIYR
  RYAGLYFCICVDVNDNNLAYLEAIHNFVEVLNEYFHNVCELDLVFNFYKVYTVVDEMFLA
  GEIRETSQTKVLKQLLMLQSLE
• Function: Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif. May also play a role in extracellular calcium homeostasis.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Retrograde neurotrophin signalling (R-HSA-177504)
  Nef Mediated CD8 Down-regulation (R-HSA-182218)
  MHC class II antigen presentation (R-HSA-2132295)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Recycling pathway of L1 (R-HSA-437239)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  VLDLR internalisation and degradation (R-HSA-8866427)
  LDL clearance (R-HSA-8964038)
  Potential therapeutics for SARS (R-HSA-9679191)
  Nef Mediated CD4 Down-regulation (R-HSA-167590)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypocalciuric hypercalcemia 3	DISTIR0K	Strong	Autosomal dominant	[1]
Familial primary hyperparathyroidism	DIS6NA55	Strong	Biomarker	[2]
Hyperparathyroidism	DIS4FVAT	Strong	Genetic Variation	[3]
Hypocalcemia	DISTCK2W	Strong	Genetic Variation	[4]
Hypoparathyroidism	DISICS0V	Strong	Genetic Variation	[5]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[6]
Primary hyperparathyroidism	DISB4U1Q	Strong	Genetic Variation	[7]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[1]
Hypercalcaemia	DISKQ2K7	Limited	Genetic Variation	[8]

12 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-2 complex subunit sigma (AP2S1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of AP-2 complex subunit sigma (AP2S1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of AP-2 complex subunit sigma (AP2S1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-2 complex subunit sigma (AP2S1).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of AP-2 complex subunit sigma (AP2S1).	[14]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of AP-2 complex subunit sigma (AP2S1).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of AP-2 complex subunit sigma (AP2S1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of AP-2 complex subunit sigma (AP2S1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of AP-2 complex subunit sigma (AP2S1).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of AP-2 complex subunit sigma (AP2S1).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of AP-2 complex subunit sigma (AP2S1).	[20]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of AP-2 complex subunit sigma (AP2S1).	[21]

2 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-2 complex subunit sigma (AP2S1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of AP-2 complex subunit sigma (AP2S1).	[16]

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] Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia.Endocrine. 2017 Mar;55(3):741-747. doi: 10.1007/s12020-017-1241-5. Epub 2017 Feb 7.
• [3] Diseases associated with calcium-sensing receptor.Orphanet J Rare Dis. 2017 Jan 25;12(1):19. doi: 10.1186/s13023-017-0570-z.
• [4] Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).J Clin Endocrinol Metab. 2014 Jul;99(7):E1300-5. doi: 10.1210/jc.2013-3909. Epub 2014 Apr 7.
• [5] Analysis of AP2S1, a calcium-sensing receptor regulator, in familial and sporadic isolated hypoparathyroidism.J Clin Endocrinol Metab. 2014 Mar;99(3):E469-73. doi: 10.1210/jc.2013-3136. Epub 2014 Jan 1.
• [6] Cinacalcet sustainedly prevents pancreatitis in a child with a compound heterozygous SPINK1/AP2S1 mutation.Pancreatology. 2019 Sep;19(6):801-804. doi: 10.1016/j.pan.2019.07.045. Epub 2019 Jul 30.
• [7] AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia.Eur J Endocrinol. 2017 Feb;176(2):177-185. doi: 10.1530/EJE-16-0842. Epub 2016 Nov 15.
• [8] Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.J Clin Endocrinol Metab. 2015 Jul;100(7):2515-8. doi: 10.1210/jc.2015-1518. Epub 2015 May 20.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.