Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT66PF24)

• DOT Name: Pleckstrin homology domain-containing family A member 1 (PLEKHA1)
• Synonyms: PH domain-containing family A member 1; Tandem PH domain-containing protein 1; TAPP-1
• Gene Name: PLEKHA1
• Related Disease:
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Glycogen storage disease type II
  Hypothyroidism
  Osteoporosis
  STAT3-related early-onset multisystem autoimmune disease
  Immune system disorder
  Non-insulin dependent diabetes
  Type-1 diabetes
• UniProt ID: PKHA1_HUMAN
• PDB ID: 1EAZ
• Pfam ID: PF00169
• Sequence:
  MPYVDRQNRICGFLDIEENENSGKFLRRYFILDTREDSFVWYMDNPQNLPSGSSRVGAIK
  LTYISKVSDATKLRPKAEFCFVMNAGMRKYFLQANDQQDLVEWVNVLNKAIKITVPKQSD
  SQPNSDNLSRHGECGKKQVSYRTDIVGGVPIITPTQKEEVNECGESIDRNNLKRSQSHLP
  YFTPKPPQDSAVIKAGYCVKQGAVMKNWKRRYFQLDENTIGYFKSELEKEPLRVIPLKEV
  HKVQECKQSDIMMRDNLFEIVTTSRTFYVQADSPEEMHSWIKAVSGAIVAQRGPGRSASS
  EHPPGPSESKHAFRPTNAATATSHSTASRSNSLVSTFTMEKRGFYESLAKVKPGNFKVQT
  VSPREPASKVTEQALLRPQSKNGPQEKDCDLVDLDDASLPVSDV
• Function: Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane.
• Tissue Specificity: Highly expressed in skeletal muscle, thymus, pancreas, placenta and lung. Detected at low levels in brain, heart, peripheral blood leukocytes, testis, ovary, spinal cord, thyroid, kidney, liver, small intestine and colon.
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[1]
Glycogen storage disease type II	DISXZPBC	Strong	Genetic Variation	[2]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[1]
Osteoporosis	DISF2JE0	Strong	Biomarker	[3]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[1]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Genetic Variation	[5]
Type-1 diabetes	DIS7HLUB	Disputed	Genetic Variation	[6]

3 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 Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pleckstrin homology domain-containing family A member 1 (PLEKHA1).	[18]

References

• [1] 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.
• [2] The NEI/NCBI dbGAP database: genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration.BMC Med Genet. 2008 Jun 9;9:51. doi: 10.1186/1471-2350-9-51.
• [3] Identification of novel variants associated with osteoporosis, type 2 diabetes and potentially pleiotropic loci using pleiotropic cFDR method.Bone. 2018 Dec;117:6-14. doi: 10.1016/j.bone.2018.08.020. Epub 2018 Aug 30.
• [4] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [5] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [6] Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.J Autoimmun. 2018 May;89:90-100. doi: 10.1016/j.jaut.2017.12.008. Epub 2018 Jan 5.
• [7] 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.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [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] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.