Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA7CG42)

• DOT Name: Peptidylprolyl isomerase domain and WD repeat-containing protein 1 (PPWD1)
• Synonyms: EC 5.2.1.8; Spliceosome-associated cyclophilin
• Gene Name: PPWD1
• Related Disease:
  Metastatic malignant neoplasm
  Neuroendocrine neoplasm
  Postmenopausal osteoporosis
  Tourette syndrome
• UniProt ID: PPWD1_HUMAN
• PDB ID: 2A2N; 5YZG; 7A5P
• EC Number: 5.2.1.8
• Pfam ID: PF00160 ; PF00400
• Sequence:
  MAAESGSDFQQRRRRRRDPEEPEKTELSERELAVAVAVSQENDEENEERWVGPLPVEATL
  AKKRKVLEFERVYLDNLPSASMYERSYMHRDVITHVVCTKTDFIITASHDGHVKFWKKIE
  EGIEFVKHFRSHLGVIESIAVSSEGALFCSVGDDKAMKVFDVVNFDMINMLKLGYFPGQC
  EWIYCPGDAISSVAASEKSTGKIFIYDGRGDNQPLHIFDKLHTSPLTQIRLNPVYKAVVS
  SDKSGMIEYWTGPPHEYKFPKNVNWEYKTDTDLYEFAKCKAYPTSVCFSPDGKKIATIGS
  DRKVRIFRFVTGKLMRVFDESLSMFTELQQMRQQLPDMEFGRRMAVERELEKVDAVRLIN
  IVFDETGHFVLYGTMLGIKVINVETNRCVRILGKQENIRVMQLALFQGIAKKHRAATTIE
  MKASENPVLQNIQADPTIVCTSFKKNRFYMFTKREPEDTKSADSDRDVFNEKPSKEEVMA
  ATQAEGPKRVSDSAIIHTSMGDIHTKLFPVECPKTVENFCVHSRNGYYNGHTFHRIIKGF
  MIQTGDPTGTGMGGESIWGGEFEDEFHSTLRHDRPYTLSMANAGSNTNGSQFFITVVPTP
  WLDNKHTVFGRVTKGMEVVQRISNVKVNPKTDKPYEDVSIINITVK
• Function: PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. May be involved in pre-mRNA splicing.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[1]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[1]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[2]
Tourette syndrome	DISX9D54	No Known	Unknown	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Peptidylprolyl isomerase domain and WD repeat-containing protein 1 (PPWD1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peptidylprolyl isomerase domain and WD repeat-containing protein 1 (PPWD1).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Peptidylprolyl isomerase domain and WD repeat-containing protein 1 (PPWD1).	[7]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Peptidylprolyl isomerase domain and WD repeat-containing protein 1 (PPWD1).	[6]

References

• [1] The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.Clin Exp Metastasis. 2014 Oct;31(7):817-27. doi: 10.1007/s10585-014-9672-3. Epub 2014 Aug 7.
• [2] PPWD1 is associated with the occurrence of postmenopausal osteoporosis as determined by weighted gene coexpression network analysis.Mol Med Rep. 2019 Oct;20(4):3202-3214. doi: 10.3892/mmr.2019.10570. Epub 2019 Aug 7.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [7] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.