Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRCPCD2)

• DOT Name: Beta-adducin (ADD2)
• Synonyms: Erythrocyte adducin subunit beta
• Gene Name: ADD2
• Related Disease:
  Hereditary spherocytosis type 1
  Anemia
  Colorectal carcinoma
  Dehydrated hereditary stomatocytosis
  Endometrial cancer
  Endometrial carcinoma
  Essential hypertension
  Hemolytic anemia
  Hereditary elliptocytosis
  High blood pressure
  IgA nephropathy
  Schizophrenia
  Urticaria
  Dilated cardiomyopathy
  Lupus
  Lupus nephritis
  Systemic lupus erythematosus
  Acute myelogenous leukaemia
  Diabetic kidney disease
  Tourette syndrome
  Type-1 diabetes
• UniProt ID: ADDB_HUMAN
• Pfam ID: PF00596
• Sequence:
  MSEETVPEAASPPPPQGQPYFDRFSEDDPEYMRLRNRAADLRQDFNLMEQKKRVTMILQS
  PSFREELEGLIQEQMKKGNNSSNIWALRQIADFMASTSHAVFPTSSMNVSMMTPINDLHT
  ADSLNLAKGERLMRCKISSVYRLLDLYGWAQLSDTYVTLRVSKEQDHFLISPKGVSCSEV
  TASSLIKVNILGEVVEKGSSCFPVDTTGFCLHSAIYAARPDVRCIIHLHTPATAAVSAMK
  WGLLPVSHNALLVGDMAYYDFNGEMEQEADRINLQKCLGPTCKILVLRNHGVVALGDTVE
  EAFYKIFHLQAACEIQVSALSSAGGVENLILLEQEKHRPHEVGSVQWAGSTFGPMQKSRL
  GEHEFEALMRMLDNLGYRTGYTYRHPFVQEKTKHKSEVEIPATVTAFVFEEDGAPVPALR
  QHAQKQQKEKTRWLNTPNTYLRVNVADEVQRSMGSPRPKTTWMKADEVEKSSSGMPIRIE
  NPNQFVPLYTDPQEVLEMRNKIREQNRQDVKSAGPQSQLLASVIAEKSRSPSTESQLMSK
  GDEDTKDDSEETVPNPFSQLTDQELEEYKKEVERKKLELDGEKETAPEEPGSPAKSAPAS
  PVQSPAKEAETKSPLVSPSKSLEEGTKKTETSKAATTEPETTQPEGVVVNGREEEQTAEE
  ILSKGLSQMTTSADTDVDTSKDKTESVTSGPMSPEGSPSKSPSKKKKKFRTPSFLKKSKK
  KEKVES
• Function: Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to the erythrocyte membrane receptor SLC2A1/GLUT1 and may therefore provide a link between the spectrin cytoskeleton to the plasma membrane. Binds to calmodulin. Calmodulin binds preferentially to the beta subunit.
• Tissue Specificity: Expressed mainly in brain, spleen, kidney cortex and medulla, and heart. Also expressed in human umbilical vein endothelial cells, human vascular smooth muscle cells, kidney tubular cells and K-562 cell line.
• Reactome Pathway: Miscellaneous transport and binding events (R-HSA-5223345)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary spherocytosis type 1	DIS34V1Z	Definitive	Biomarker	[1]
Anemia	DISTVL0C	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Dehydrated hereditary stomatocytosis	DISGQT6H	Strong	Genetic Variation	[4]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[5]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[5]
Essential hypertension	DIS7WI98	Strong	Biomarker	[6]
Hemolytic anemia	DIS803XQ	Strong	Biomarker	[7]
Hereditary elliptocytosis	DISA71F4	Strong	Altered Expression	[8]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[9]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[11]
Urticaria	DIS9WQAI	Strong	Altered Expression	[12]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[13]
Lupus	DISOKJWA	moderate	Genetic Variation	[14]
Lupus nephritis	DISCVGPZ	moderate	Genetic Variation	[14]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[14]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[15]
Diabetic kidney disease	DISJMWEY	Limited	Genetic Variation	[16]
Tourette syndrome	DISX9D54	Limited	Biomarker	[17]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[16]

1 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 Beta-adducin (ADD2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-adducin (ADD2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-adducin (ADD2).	[20]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Beta-adducin (ADD2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Beta-adducin (ADD2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Beta-adducin (ADD2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Beta-adducin (ADD2).	[24]

References

• [1] Targeted deletion of the gamma-adducin gene (Add3) in mice reveals differences in alpha-adducin interactions in erythroid and nonerythroid cells.Am J Hematol. 2009 Jun;84(6):354-61. doi: 10.1002/ajh.21427.
• [2] Haematological phenotypes in relation to the C1797T beta-adducin polymorphism in a Caucasian population.Clin Sci (Lond). 2003 Apr;104(4):369-76.
• [3] Discovery and Validation of Hypermethylated Markers for Colorectal Cancer.Dis Markers. 2016;2016:2192853. doi: 10.1155/2016/2192853. Epub 2016 Jul 14.
• [4] Exclusion of the stomatin, alpha-adducin and beta-adducin loci in a large kindred with dehydrated hereditary stomatocytosis.Am J Hematol. 1999 Jan;60(1):72-4. doi: 10.1002/(sici)1096-8652(199901)60:1<72::aid-ajh13>3.0.co;2-8.
• [5] MiR-218 suppresses metastasis and invasion of endometrial cancer via negatively regulating ADD2.Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1408-1417. doi: 10.26355/eurrev_201902_17097.
• [6] Polymorphisms in four candidate genes in young patients with essential hypertension.Acta Paediatr. 2006 Mar;95(3):353-8. doi: 10.1080/08035250500434777.
• [7] Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia.J Biol Chem. 2007 Feb 9;282(6):4124-35. doi: 10.1074/jbc.M610231200. Epub 2006 Dec 2.
• [8] Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice.Blood. 2000 Jun 15;95(12):3978-85.
• [9] Intra-erythrocyte cation concentrations in relation to the C1797T beta-adducin polymorphism in a general population.J Hum Hypertens. 2007 May;21(5):387-92. doi: 10.1038/sj.jhh.1002154. Epub 2007 Feb 15.
• [10] alpha- and beta-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy.J Mol Med (Berl). 2010 Feb;88(2):203-17. doi: 10.1007/s00109-009-0549-x. Epub 2009 Oct 17.
• [11] ADDing a piece to the puzzle of cognition in schizophrenia.Eur J Med Genet. 2016 Jan;59(1):26-31. doi: 10.1016/j.ejmg.2015.12.012. Epub 2015 Dec 24.
• [12] Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis.J Neuroimmunol. 2004 Dec;157(1-2):163-75. doi: 10.1016/j.jneuroim.2004.08.026.
• [13] Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.PLoS Genet. 2010 Oct 21;6(10):e1001167. doi: 10.1371/journal.pgen.1001167.
• [14] Beta-adducin and sodium-calcium exchanger 1 gene variants are associated with systemic lupus erythematosus and lupus nephritis.Rheumatol Int. 2015 Dec;35(12):1975-83. doi: 10.1007/s00296-015-3298-x. Epub 2015 Jun 5.
• [15] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [16] Investigation of Adducin 2 (beta) DNA polymorphisms in genetic predisposition to diabetic nephropathy in Type 1 diabetes.Diabet Med. 2008 Aug;25(8):1001-5. doi: 10.1111/j.1464-5491.2008.02511.x.
• [17] A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems.Am J Hum Genet. 1987 Nov;41(5):701-41.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [22] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [23] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [24] 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.