Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWVRR35)

• DOT Name: Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1)
• Synonyms: GPI anchor attachment protein 1; GAA1 protein homolog; hGAA1
• Gene Name: GPAA1
• Related Disease:
  Alzheimer disease
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Friedreich's ataxia
  Glycosylphosphatidylinositol biosynthesis defect 15
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Invasive breast carcinoma
  Liver cirrhosis
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Neoplasm
  Advanced cancer
  Friedreich ataxia 1
  Gastric cancer
  Metastatic malignant neoplasm
  Stomach cancer
• UniProt ID: GPAA1_HUMAN
• PDB ID: 7W72; 7WLD; 8IMX; 8IMY
• Pfam ID: PF04114
• Sequence:
  MGLLSDPVRRRALARLVLRLNAPLCVLSYVAGIAWFLALVFPPLTQRTYMSENAMGSTMV
  EEQFAGGDRARAFARDFAAHRKKSGALPVAWLERTMRSVGLEVYTQSFSRKLPFPDETHE
  RYMVSGTNVYGILRAPRAASTESLVLTVPCGSDSTNSQAVGLLLALAAHFRGQIYWAKDI
  VFLVTEHDLLGTEAWLEAYHDVNVTGMQSSPLQGRAGAIQAAVALELSSDVVTSLDVAVE
  GLNGQLPNLDLLNLFQTFCQKGGLLCTLQGKLQPEDWTSLDGPLQGLQTLLLMVLRQASG
  RPHGSHGLFLRYRVEALTLRGINSFRQYKYDLVAVGKALEGMFRKLNHLLERLHQSFFLY
  LLPGLSRFVSIGLYMPAVGFLLLVLGLKALELWMQLHEAGMGLEEPGGAPGPSVPLPPSQ
  GVGLASLVAPLLISQAMGLALYVLPVLGQHVATQHFPVAEAEAVVLTLLAIYAAGLALPH
  NTHRVVSTQAPDRGWMALKLVALIYLALQLGCIALTNFSLGFLLATTMVPTAALAKPHGP
  RTLYAALLVLTSPAATLLGSLFLWRELQEAPLSLAEGWQLFLAALAQGVLEHHTYGALLF
  PLLSLGLYPCWLLFWNVLFWK
• Function: Component of the GPI transamidase complex, necessary for transfer of GPI to proteins. Essential for GPI-anchoring of precursor proteins but not for GPI synthesis. Acts before or during formation of the carbonyl intermediate.
• Tissue Specificity: Ubiquitously expressed in fetal and adult tissues. Expressed at higher levels in fetal tissues than adult tissues.
• KEGG Pathway:
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Attachment of GPI anchor to uPAR (R-HSA-162791)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Friedreich's ataxia	DIS5DV35	Strong	Genetic Variation	[4]
Glycosylphosphatidylinositol biosynthesis defect 15	DIS4X154	Strong	Autosomal recessive	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Invasive breast carcinoma	DISANYTW	Strong	Altered Expression	[8]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[6]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Altered Expression	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[9]
Friedreich ataxia 1	DIS285GE	Limited	Genetic Variation	[10]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[9]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1) affects the response to substance of Cisplatin.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[18]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Glycosylphosphatidylinositol anchor attachment 1 protein (GPAA1).	[19]

References

• [1] Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.JAMA Neurol. 2019 Sep 1;76(9):1099-1108. doi: 10.1001/jamaneurol.2019.1456.
• [2] Profiling the expression pattern of GPI transamidase complex subunits in human cancer.Mod Pathol. 2008 Aug;21(8):979-91. doi: 10.1038/modpathol.2008.76. Epub 2008 May 16.
• [3] Enhanced expression and significance of glycosylphosphatidylinositol anchor attachment protein 1 in colorectal cancer.Genet Mol Res. 2014 Jan 21;13(1):499-507. doi: 10.4238/2014.January.21.19.
• [4] Very late-onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type.Mov Disord. 2005 Dec;20(12):1643-5. doi: 10.1002/mds.20644.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Alterations of GPI transamidase subunits in head and neck squamous carcinoma.Mol Cancer. 2007 Nov 21;6:74. doi: 10.1186/1476-4598-6-74.
• [7] Increased expression of glycosyl-phosphatidylinositol anchor attachment protein 1 (GPAA1) is associated with gene amplification in hepatocellular carcinoma.Int J Cancer. 2006 Sep 15;119(6):1330-7. doi: 10.1002/ijc.22005.
• [8] Overexpression of glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer.Cancer Res. 2006 Oct 15;66(20):9829-36. doi: 10.1158/0008-5472.CAN-06-0506.
• [9] GPAA1 promotes gastric cancer progression via upregulation of GPI-anchored protein and enhancement of ERBB signalling pathway.J Exp Clin Cancer Res. 2019 May 22;38(1):214. doi: 10.1186/s13046-019-1218-8.
• [10] Left ventricular structural and functional changes in Friedreich ataxia - Relationship with body size, sex, age and genetic severity.PLoS One. 2019 Nov 13;14(11):e0225147. doi: 10.1371/journal.pone.0225147. eCollection 2019.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [18] 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.
• [19] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.