Details of Drug Off-Target (DOT)

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

• DOT Name: Mitochondrial-processing peptidase subunit beta (PMPCB)
• Synonyms: EC 3.4.24.64; Beta-MPP; P-52
• Gene Name: PMPCB
• Related Disease:
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Multiple mitochondrial dysfunctions syndrome 6
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: MPPB_HUMAN
• EC Number: 3.4.24.64
• Pfam ID: PF00675 ; PF05193
• Sequence:
  MAAAAARVVLSSAARRRLWGFSESLLIRGAAGRSLYFGENRLRSTQAATQVVLNVPETRV
  TCLESGLRVASEDSGLSTCTVGLWIDAGSRYENEKNNGTAHFLEHMAFKGTKKRSQLDLE
  LEIENMGAHLNAYTSREQTVYYAKAFSKDLPRAVEILADIIQNSTLGEAEIERERGVILR
  EMQEVETNLQEVVFDYLHATAYQNTALGRTILGPTENIKSISRKDLVDYITTHYKGPRIV
  LAAAGGVSHDELLDLAKFHFGDSLCTHKGEIPALPPCKFTGSEIRVRDDKMPLAHLAIAV
  EAVGWAHPDTICLMVANTLIGNWDRSFGGGMNLSSKLAQLTCHGNLCHSFQSFNTSYTDT
  GLWGLYMVCESSTVADMLHVVQKEWMRLCTSVTESEVARARNLLKTNMLLQLDGSTPICE
  DIGRQMLCYNRRIPIPELEARIDAVNAETIREVCTKYIYNRSPAIAAVGPIKQLPDFKQI
  RSNMCWLRD
• Function: Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins (Probable). Preferentially, cleaves after an arginine at position P2. Required for PINK1 turnover by coupling PINK1 mitochondrial import and cleavage, which results in subsequent PINK1 proteolysis.
• Reactome Pathway:
  Processing of SMDT1 (R-HSA-8949664)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Multiple mitochondrial dysfunctions syndrome 6	DISN3J4U	Strong	Autosomal recessive	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[1]

12 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 Mitochondrial-processing peptidase subunit beta (PMPCB).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial-processing peptidase subunit beta (PMPCB).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitochondrial-processing peptidase subunit beta (PMPCB).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mitochondrial-processing peptidase subunit beta (PMPCB).	[14]

References

• [1] A putative oncogenic role for MPP11 in head and neck squamous cell cancer.Cancer Res. 2000 Oct 1;60(19):5529-35.
• [2] Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM(+) Hepatocellular Carcinoma.Cancer Res. 2019 May 1;79(9):2379-2391. doi: 10.1158/0008-5472.CAN-18-3015. Epub 2019 Mar 12.
• [3] Is misoprostol prophylaxis indicated for NSAID induced adverse gastrointestinal events? An epidemiologic opinion. J Rheumatol. 1991 Jul;18(7):958-61.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] 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.
• [7] 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.
• [8] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.