Details of Drug Off-Target (DOT)

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

• DOT Name: ]-phosphatase 2, mitochondrial (PDP2)
• Synonyms: PDP 2; EC 3.1.3.43; Pyruvate dehydrogenase phosphatase catalytic subunit 2; PDPC 2
• Gene Name: PDP2
• Related Disease:
  Nervous system inflammation
  Systemic lupus erythematosus
• UniProt ID: PDP2_HUMAN
• EC Number: 3.1.3.43
• Pfam ID: PF00481
• Sequence:
  MSSTVSYWILNSTRNSIATLQGGRRLYSRYVSNRNKLKWRLFSRVPPTLNSSPCGGFTLC
  KAYRHTSTEEDDFHLQLSPEQINEVLRAGETTHKILDLESRVPNSVLRFESNQLAANSPV
  EDRRGVASCLQTNGLMFGIFDGHGGHACAQAVSERLFYYVAVSLMSHQTLEHMEGAMESM
  KPLLPILHWLKHPGDSIYKDVTSVHLDHLRVYWQELLDLHMEMGLSIEEALMYSFQRLDS
  DISLEIQAPLEDEVTRNLSLQVAFSGATACMAHVDGIHLHVANAGDCRAILGVQEDNGMW
  SCLPLTRDHNAWNQAELSRLKREHPESEDRTIIMEDRLLGVLIPCRAFGDVQLKWSKELQ
  RSILERGFNTEALNIYQFTPPHYYTPPYLTAEPEVTYHRLRPQDKFLVLASDGLWDMLSN
  EDVVRLVVGHLAEADWHKTDLAQRPANLGLMQSLLLQRKASGLHEADQNAATRLIRHAIG
  NNEYGEMEAERLAAMLTLPEDLARMYRDDITVTVVYFNSESIGAYYKGG
• Function: Mitochondrial enzyme that catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex (PDC), thereby stimulating the conversion of pyruvate into acetyl-CoA. Acts as a crucial regulator of T cell metabolism and function, with a particular focus on T-helper Th17.
• Reactome Pathway: Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[1]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[7]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[2]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[12]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of ]-phosphatase 2, mitochondrial (PDP2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of ]-phosphatase 2, mitochondrial (PDP2).	[11]

References

• [1] Pyruvate dehydrogenase phosphatase catalytic subunit 2 limits Th17 differentiation.Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9288-9293. doi: 10.1073/pnas.1805717115. Epub 2018 Aug 27.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.
• [11] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.