Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL73AO8)

• DOT Name: Protein disulfide isomerase CRELD2 (CRELD2)
• Synonyms: EC 5.3.4.1; Cysteine-rich with EGF-like domain protein 2
• Gene Name: CRELD2
• Related Disease:
  Juvenile polyposis syndrome
  Multiple epiphyseal dysplasia
  Autosomal dominant medullary cystic kidney disease with or without hyperuricemia
  Nephropathy
  Nephrotic syndrome
• UniProt ID: CREL2_HUMAN
• EC Number: 5.3.4.1
• Pfam ID: PF07645
• Sequence:
  MRLPRRAALGLLPLLLLLPPAPEAAKKPTPCHRCRGLVDKFNQGMVDTAKKNFGGGNTAW
  EEKTLSKYESSEIRLLEILEGLCESSDFECNQMLEAQEEHLEAWWLQLKSEYPDLFEWFC
  VKTLKVCCSPGTYGPDCLACQGGSQRPCSGNGHCSGDGSRQGDGSCRCHMGYQGPLCTDC
  MDGYFSSLRNETHSICTACDESCKTCSGLTNRDCGECEVGWVLDEGACVDVDECAAEPPP
  CSAAQFCKNANGSYTCEECDSSCVGCTGEGPGNCKECISGYAREHGQCADVDECSLAEKT
  CVRKNENCYNTPGSYVCVCPDGFEETEDACVPPAEAEATEGESPTQLPSREDL
• Function: Protein disulfide isomerase. Might play a role in the unfolded protein response. May regulate transport of alpha4-beta2 neuronal acetylcholine receptor.
• Tissue Specificity: Ubiquitously expressed . Highly expressed in skeletal muscle, heart, liver, kidney and placenta .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Juvenile polyposis syndrome	DISBPSLH	Strong	Biomarker	[1]
Multiple epiphyseal dysplasia	DIS5FZLR	Strong	Biomarker	[2]
Autosomal dominant medullary cystic kidney disease with or without hyperuricemia	DIS3PLLZ	moderate	Genetic Variation	[3]
Nephropathy	DISXWP4P	moderate	Biomarker	[4]
Nephrotic syndrome	DISSPSC2	moderate	Biomarker	[3]

2 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 CRELD2 (CRELD2).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein disulfide isomerase CRELD2 (CRELD2).	[11]

8 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 CRELD2 (CRELD2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein disulfide isomerase CRELD2 (CRELD2).	[14]

References

• [1] Synovial fluid interleukin-16, interleukin-18, and CRELD2 as novel biomarkers of prosthetic joint infections.Bone Joint Res. 2019 May 3;8(4):179-188. doi: 10.1302/2046-3758.84.BJR-2018-0291.R1. eCollection 2019 Apr.
• [2] Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for ... Hum Mol Genet. 2013 Dec 20;22(25):5262-75.
• [3] Elevated urinary CRELD2 is associated with endoplasmic reticulum stress-mediated kidney disease.JCI Insight. 2017 Dec 7;2(23):e92896. doi: 10.1172/jci.insight.92896.
• [4] Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology.Pediatr Nephrol. 2019 Sep;34(9):1493-1500. doi: 10.1007/s00467-018-4031-2. Epub 2018 Aug 11.
• [5] 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.
• [6] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] 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.
• [9] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [10] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.