Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC2WMXS)

• DOT Name: Protein disulfide-isomerase A2 (PDIA2)
• Synonyms: EC 5.3.4.1; Pancreas-specific protein disulfide isomerase; PDIp
• Gene Name: PDIA2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Behcet disease
  Hermansky-Pudlak syndrome
  High blood pressure
  Insulinoma
  Myopia
  Non-small-cell lung cancer
  Osteogenesis imperfecta
  Osteoporosis
  Schizophrenia
  Visceral leishmaniasis
  Amyotrophic lateral sclerosis
  Bacterial infection
  Hepatocellular carcinoma
  Hypoglycemia
  Plasma cell myeloma
  Type-1/2 diabetes
  Anxiety
  Anxiety disorder
  Breast cancer
  Breast carcinoma
  Depression
  Neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Parkinson disease
• UniProt ID: PDIA2_HUMAN
• EC Number: 5.3.4.1
• Pfam ID: PF00085 ; PF13848
• Sequence:
  MSRQLLPVLLLLLLRASCPWGQEQGARSPSEEPPEEEIPKEDGILVLSRHTLGLALREHP
  ALLVEFYAPWCGHCQALAPEYSKAAAVLAAESMVVTLAKVDGPAQRELAEEFGVTEYPTL
  KFFRNGNRTHPEEYTGPRDAEGIAEWLRRRVGPSAMRLEDEAAAQALIGGRDLVVIGFFQ
  DLQDEDVATFLALAQDALDMTFGLTDRPRLFQQFGLTKDTVVLFKKFDEGRADFPVDEEL
  GLDLGDLSRFLVTHSMRLVTEFNSQTSAKIFAARILNHLLLFVNQTLAAHRELLAGFGEA
  APRFRGQVLFVVVDVAADNEHVLQYFGLKAEAAPTLRLVNLETTKKYAPVDGGPVTAASI
  TAFCHAVLNGQVKPYLLSQEIPPDWDQRPVKTLVGKNFEQVAFDETKNVFVKFYAPWCTH
  CKEMAPAWEALAEKYQDHEDIIIAELDATANELDAFAVHGFPTLKYFPAGPGRKVIEYKS
  TRDLETFSKFLDNGGVLPTEEPPEEPAAPFPEPPANSTMGSKEEL
• Function: Acts as an intracellular estrogen-binding protein. May be involved in modulating cellular levels and biological functions of estrogens in the pancreas. May act as a chaperone that inhibits aggregation of misfolded proteins.
• Tissue Specificity: Highly expressed in pancreas (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Behcet disease	DISSYMBS	Strong	Biomarker	[4]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Insulinoma	DISIU1JS	Strong	Altered Expression	[6]
Myopia	DISK5S60	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Osteogenesis imperfecta	DIS7XQSD	Strong	Altered Expression	[9]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Visceral leishmaniasis	DISTKEYK	Strong	Biomarker	[12]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Genetic Variation	[13]
Bacterial infection	DIS5QJ9S	moderate	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[15]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[16]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[18]
Anxiety	DISIJDBA	Limited	Genetic Variation	[19]
Anxiety disorder	DISBI2BT	Limited	Genetic Variation	[19]
Breast cancer	DIS7DPX1	Limited	Biomarker	[20]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[20]
Depression	DIS3XJ69	Limited	Genetic Variation	[21]
Neoplasm	DISZKGEW	Limited	Biomarker	[22]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[24]
Parkinson disease	DISQVHKL	Limited	Biomarker	[23]

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 Protein disulfide-isomerase A2 (PDIA2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein disulfide-isomerase A2 (PDIA2).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein disulfide-isomerase A2 (PDIA2).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Protein disulfide-isomerase A2 (PDIA2).	[28]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protein disulfide-isomerase A2 (PDIA2).	[29]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Protein disulfide-isomerase A2 (PDIA2).	[30]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Protein disulfide-isomerase A2 (PDIA2).	[31]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Protein disulfide-isomerase A2 (PDIA2).	[32]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Protein disulfide-isomerase A2 (PDIA2).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein disulfide-isomerase A2 (PDIA2).	[34]

References

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• [2] Small Molecule Inhibition of Protein Disulfide Isomerase in Neuroblastoma Cells Induces an Oxidative Stress Response and Apoptosis Pathways.ACS Chem Neurosci. 2019 Sep 18;10(9):4068-4075. doi: 10.1021/acschemneuro.9b00301. Epub 2019 Aug 8.
• [3] Operational Differences in Plant-Based Diet Indices Affect the Ability to Detect Associations with Incident Hypertension in Middle-Aged US Adults.J Nutr. 2020 Apr 1;150(4):842-850. doi: 10.1093/jn/nxz275.
• [4] One-Year Developmental Outcomes for Infants of Mothers With Bipolar Disorder.J Clin Psychiatry. 2017 Sep-Oct;78(8):1083-1090. doi: 10.4088/JCP.15m10535.
• [5] Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome.Blood. 2015 Mar 5;125(10):1633-42. doi: 10.1182/blood-2014-08-597419. Epub 2015 Jan 15.
• [6] IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic cells.J Cell Biol. 2018 Apr 2;217(4):1287-1301. doi: 10.1083/jcb.201707143. Epub 2018 Mar 5.
• [7] Performance of a Quick Screening Version of the Nintendo 3DS PDI Check Game in Patients With Ocular Suppression.J Pediatr Ophthalmol Strabismus. 2019 Jul 1;56(4):234-237. doi: 10.3928/01913913-20190502-01.
• [8] Combined expression of protein disulfide isomerase and endoplasmic reticulum oxidoreductin 1- is a poor prognostic marker for non-small cell lung cancer.Oncol Lett. 2018 Nov;16(5):5753-5760. doi: 10.3892/ol.2018.9339. Epub 2018 Aug 21.
• [9] NOVEL MUTATIONS IN THE WNT1, TMEM38B, P4HB, AND PLS3 GENES IN FOUR UNRELATED CHINESE FAMILIES WITH OSTEOGENESIS IMPERFECTA. Endocr Pract. 2019 Mar;25(3):230-241. doi: 10.4158/EP-2018-0443.
• [10] Regulation of ER molecular chaperone prevents bone loss in a murine model for osteoporosis.J Bone Miner Metab. 2010 Mar;28(2):131-8. doi: 10.1007/s00774-009-0117-z. Epub 2009 Sep 17.
• [11] Invariance of factor structure of the 21-item Peters et al. Delusions Inventory (PDI-21) over time and across samples.Psychiatry Res. 2017 Aug;254:190-197. doi: 10.1016/j.psychres.2017.04.053. Epub 2017 Apr 24.
• [12] Bioinformatics analysis of four proteins of Leishmania donovani to guide epitopes vaccine design and drug targets selection.Acta Trop. 2019 Mar;191:50-59. doi: 10.1016/j.actatropica.2018.12.035. Epub 2018 Dec 21.
• [13] ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis.Hum Mol Genet. 2018 Apr 15;27(8):1311-1331. doi: 10.1093/hmg/ddy041.
• [14] Perylenediimide-based glycoclusters as high affinity ligands of bacterial lectins: synthesis, binding studies and anti-adhesive properties.Org Biomol Chem. 2017 Dec 6;15(47):10037-10043. doi: 10.1039/c7ob02749d.
• [15] Microvascular Flow Imaging of Residual or Recurrent Hepatocellular Carcinoma after Transarterial Chemoembolization: Comparison with Color/Power Doppler Imaging.Korean J Radiol. 2019 Jul;20(7):1114-1123. doi: 10.3348/kjr.2018.0932.
• [16] Anxiety affects disability and quality of life in patients with painful diabetic neuropathy.Eur J Pain. 2017 Nov;21(10):1632-1641. doi: 10.1002/ejp.1067. Epub 2017 Jun 27.
• [17] Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor.Eur J Med Chem. 2020 Jan 15;186:111906. doi: 10.1016/j.ejmech.2019.111906. Epub 2019 Nov 21.
• [18] Transcriptional regulation of rat liver protein disulphide-isomerase gene by insulin and in diabetes.Biochem J. 1990 Apr 15;267(2):317-23. doi: 10.1042/bj2670317.
• [19] The pain course: a randomised controlled trial comparing a remote-delivered chronic pain management program when provided in online and workbook formats.Pain. 2017 Jul;158(7):1289-1301. doi: 10.1097/j.pain.0000000000000916.
• [20] Delivery of Amonafide from Fructose-Coated Nanodiamonds by Oxime Ligation for the Treatment of Human Breast Cancer.Biomacromolecules. 2018 Feb 12;19(2):481-489. doi: 10.1021/acs.biomac.7b01592. Epub 2018 Jan 23.
• [21] Posttraumatic stress disorder after minor trauma - A prospective cohort study.Med Hypotheses. 2020 Feb;135:109465. doi: 10.1016/j.mehy.2019.109465. Epub 2019 Nov 6.
• [22] Cancer-associated oxidoreductase ERO1- promotes immune escape through up-regulation of PD-L1 in human breast cancer.Oncotarget. 2017 Apr 11;8(15):24706-24718. doi: 10.18632/oncotarget.14960.
• [23] Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology.Brain Res. 2004 Oct 1;1022(1-2):164-72. doi: 10.1016/j.brainres.2004.07.026.
• [24] Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes.PLoS One. 2013 Apr 25;8(4):e62418. doi: 10.1371/journal.pone.0062418. Print 2013.
• [25] 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.
• [26] 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.
• [27] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [28] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [29] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [30] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [31] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [32] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [33] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [34] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.