Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL9Y4IO)

• DOT Name: RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2)
• Synonyms: EC 2.3.2.27; CYC4; Cyclophilin-60; Cyclophilin-like protein Cyp-60; Cyp60; hCyP-60; Probable inactive peptidyl-prolyl cis-trans isomerase-like 2; PPIase; Rotamase PPIL2
• Gene Name: PPIL2
• Related Disease:
  Abscess
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Gastric disease
  Parkinson disease
  Type-1 diabetes
  Amyotrophic lateral sclerosis
• UniProt ID: PPIL2_HUMAN
• PDB ID: 1ZKC; 7ABI; 7DVQ; 7QTT; 8CH6
• EC Number: 2.3.2.27
• Pfam ID: PF00160
• Sequence:
  MGKRQHQKDKMYITCAEYTHFYGGKKPDLPQTNFRRLPFDHCSLSLQPFVYPVCTPDGIV
  FDLLNIVPWLKKYGTNPSNGEKLDGRSLIKLNFSKNSEGKYHCPVLFTVFTNNTHIVAVR
  TTGNVYAYEAVEQLNIKAKNFRDLLTDEPFSRQDIITLQDPTNLDKFNVSNFYHVKNNMK
  IIDPDEEKAKQDPSYYLKNTNAETRETLQELYKEFKGDEILAATMKAPEKKKVDKLNAAH
  YSTGKVSASFTSTAMVPETTHEAAAIDEDVLRYQFVKKKGYVRLHTNKGDLNLELHCDLT
  PKTCENFIRLCKKHYYDGTIFHRSIRNFVIQGGDPTGTGTGGESYWGKPFKDEFRPNLSH
  TGRGILSMANSGPNSNRSQFFITFRSCAYLDKKHTIFGRVVGGFDVLTAMENVESDPKTD
  RPKEEIRIDATTVFVDPYEEADAQIAQERKTQLKVAPETKVKSSQPQAGSQGPQTFRQGV
  GKYINPAATKRAAEEEPSTSATVPMSKKKPSRGFGDFSSW
• Function: Has a ubiquitin-protein ligase activity acting as an E3 ubiquitin protein ligase or as an ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates. By mediating 'Lys-48'-linked polyubiquitination of proteins could target them for proteasomal degradation. May also function as a chaperone, playing a role in transport to the cell membrane of BSG/Basigin for instance. Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
• Tissue Specificity: Highest expression in thymus, pancreas and testis. Also detected in heart, placenta, lung, liver, skeletal muscle, kidney, spleen, prostate, ovary, small intestine and colon. Poorly detected in brain and leukocytes. Strong protein expression in lymph node (cortical, paracortical and medullar regions), thyroid (follicular epithelial cells), testis (developing spermatozoa), stomach (cells lining the gastric pit), pancreas, kidney (proximal and distal-tubule cells and collecting duct cells but not in glomeruli), endometrium and colon (goblet cells). Moderate protein expression in spleen, prostate (epithelium and squamous cell carcinomas), placenta and adrenal gland. Weak protein expression in liver, heart, breast, ovary, and lung. No protein expression in brain and bladder. High protein expression in most lymphomas and melanomas.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Basigin interactions (R-HSA-210991)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abscess	DISAP982	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Gastric disease	DISNZNTG	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Disputed	Genetic Variation	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RING-type E3 ubiquitin-protein ligase PPIL2 (PPIL2).	[12]

References

• [1] Novel Regulation of Alpha-Toxin and the Phenol-Soluble Modulins by Peptidyl-Prolyl cis/trans Isomerase Enzymes in Staphylococcus aureus.Toxins (Basel). 2019 Jun 16;11(6):343. doi: 10.3390/toxins11060343.
• [2] U-box ubiquitin ligase PPIL2 suppresses breast cancer invasion and metastasis by altering cell morphology and promoting SNAI1 ubiquitination and degradation.Cell Death Dis. 2018 Jan 19;9(2):63. doi: 10.1038/s41419-017-0094-4.
• [3] Differential Proteomic Analysis Reveals Protein Networks and Pathways that May Contribute to Helicobacter pylori FKBP-Type PPIase-Associated Gastric Diseases.Proteomics Clin Appl. 2018 May;12(3):e1700127. doi: 10.1002/prca.201700127. Epub 2017 Dec 5.
• [4] The Molecular Basis of the Interaction of CyclophilinA with -Synuclein.Angew Chem Int Ed Engl. 2020 Mar 27;59(14):5643-5646. doi: 10.1002/anie.201914878. Epub 2020 Jan 29.
• [5] 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.
• [6] Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis.J Neurosci. 2017 Feb 8;37(6):1413-1427. doi: 10.1523/JNEUROSCI.2462-16.2016. Epub 2016 Dec 23.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Distinct genetic profile in peripheral blood mononuclear cells of psoriatic arthritis patients treated with methotrexate and TNF-inhibitors. Clin Rheumatol. 2014 Dec;33(12):1815-21. doi: 10.1007/s10067-014-2807-8. Epub 2014 Oct 24.
• [9] 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.
• [10] 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.
• [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] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.