Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CDF7W)

• DOT Name: Peptidyl-prolyl cis-trans isomerase D (PPID)
• Synonyms: PPIase D; EC 5.2.1.8; 40 kDa peptidyl-prolyl cis-trans isomerase; Cyclophilin-40; CYP-40; Cyclophilin-related protein; Rotamase D
• Gene Name: PPID
• UniProt ID: PPID_HUMAN
• EC Number: 5.2.1.8
• Pfam ID: PF00160
• Sequence:
  MSHPSPQAKPSNPSNPRVFFDVDIGGERVGRIVLELFADIVPKTAENFRALCTGEKGIGH
  TTGKPLHFKGCPFHRIIKKFMIQGGDFSNQNGTGGESIYGEKFEDENFHYKHDREGLLSM
  ANAGRNTNGSQFFITTVPTPHLDGKHVVFGQVIKGIGVARILENVEVKGEKPAKLCVIAE
  CGELKEGDDGGIFPKDGSGDSHPDFPEDADIDLKDVDKILLITEDLKNIGNTFFKSQNWE
  MAIKKYAEVLRYVDSSKAVIETADRAKLQPIALSCVLNIGACKLKMSNWQGAIDSCLEAL
  ELDPSNTKALYRRAQGWQGLKEYDQALADLKKAQGIAPEDKAIQAELLKVKQKIKAQKDK
  EKAVYAKMFA
• Function: PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. Proposed to act as a co-chaperone in HSP90 complexes such as in unligated steroid receptors heterocomplexes. Different co-chaperones seem to compete for association with HSP90 thus establishing distinct HSP90-co-chaperone-receptor complexes with the potential to exert tissue-specific receptor activity control. May have a preference for estrogen receptor complexes and is not found in glucocorticoid receptor complexes. May be involved in cytoplasmic dynein-dependent movement of the receptor from the cytoplasm to the nucleus. May regulate MYB by inhibiting its DNA-binding activity. Involved in regulation of AHR signaling by promoting the formation of the AHR:ARNT dimer; the function is independent of HSP90 but requires the chaperone activity. Involved in regulation of UV radiation-induced apoptosis. Promotes cell viability in anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell lines; (Microbial infection) May be involved in hepatitis C virus (HCV) replication and release.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Necroptosis (hsa04217)
  Cellular senescence (hsa04218)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
• Reactome Pathway: ESR-mediated signaling (R-HSA-8939211)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[9]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peptidyl-prolyl cis-trans isomerase D (PPID).	[16]

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 Peptidyl-prolyl cis-trans isomerase D (PPID).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Peptidyl-prolyl cis-trans isomerase D (PPID).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Peptidyl-prolyl cis-trans isomerase D (PPID).	[14]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [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] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.