Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYAERF2)

• DOT Name: Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR)
• Synonyms: PDPr
• Gene Name: PDPR
• Related Disease: Arrhythmia
• UniProt ID: PDPR_HUMAN
• PDB ID: 8FHL; 8FHU
• Pfam ID: PF01266 ; PF16350 ; PF01571 ; PF08669
• Sequence:
  MMFYRLLSIVGRQRASPGWQNWSSARNSTSAAEARSMALPTQAQVVICGGGITGTSVAYH
  LSKMGWKDIVLLEQGRLAAGSTRFCAGILSTARHLTIEQKMADYSNKLYYQLEQETGIQT
  GYTRTGSIFLAQTQDRLISLKRINAGLNVIGIPSEIISPKKVAELHHLLNVHDLVGAMHV
  PEDAVVSSADVALALASAASQNGVQIYDRTSVLHVMVKKGQVTGVETDKGQIECQYFVNC
  AGQWAYELGLSNEEPVSIPLHACEHFYLLTRPLETPLQSSTPTIVDADGRIYIRNWQGGI
  LSGGFEKNPKPIFTEGKNQLEIQNLQEDWDHFEPLLSSLLRRMPELETLEIMKLVNCPET
  FTPDMRCIMGESPAVQGYFVLAGMNSAGLSFGGGAGKYLAEWMVHGYPSENVWELDLKRF
  GALQSSRTFLRHRVMEVMPLMYDLKVPRWDFQTGRQLRTSPLYDRLDAQGARWMEKHGFE
  RPKYFVPPDKDLLALEQSKTFYKPDWFDIVESEVKCCKEAVCVIDMSSFTKFEITSTGDQ
  ALEVLQYLFSNDLDVPVGHIVHTGMLNEGGGYENDCSIARLNKRSFFMISPTDQQVHCWA
  WLKKHMPKDSNLLLEDVTWKYTALNLIGPRAVDVLSELSYAPMTPDHFPSLFCKEMSVGY
  ANGIRVMSMTHTGEPGFMLYIPIEYALHVYNEVMSVGQKYGIRNAGYYALRSLRIEKFFA
  FWGQDINNLTTPLECGRESRVKLEKGMDFIGRDALLQQKQNGVYKRLTMFILDDHDSDLD
  LWPWWGEPIYRNGQYVGKTTSSAYSYSLERHVCLGFVHNFSEDTGEEQVVTADFINRGEY
  EIDIAGYRFQAKAKLYPVASLFTQKRRKDDMELSDLHGK
• Function: Decreases the sensitivity of PDP1 to magnesium ions, and this inhibition is reversed by the polyamine spermine.
• Reactome Pathway: Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmia	DISFF2NI	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[8]

2 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 Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pyruvate dehydrogenase phosphatase regulatory subunit, mitochondrial (PDPR).	[7]

References

• [1] Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca(2+) leak in human heart failure.Eur J Heart Fail. 2018 Dec;20(12):1673-1685. doi: 10.1002/ejhf.1297. Epub 2018 Sep 7.
• [2] 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.
• [3] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] Metabolomic modulations of HepG2 cells exposed to bisphenol analogues. Environ Int. 2019 Aug;129:59-67. doi: 10.1016/j.envint.2019.05.008. Epub 2019 May 20.