Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDEAZ8K)

• DOT Name: Presequence protease, mitochondrial (PITRM1)
• Synonyms: hPreP; EC 3.4.24.-; Pitrilysin metalloproteinase 1; Metalloprotease 1; hMP1
• Gene Name: PITRM1
• Related Disease:
  Intellectual disability
  Myocardial infarction
  Psychotic disorder
  Spinocerebellar ataxia, autosomal recessive 30
  Choriocarcinoma
• UniProt ID: PREP_HUMAN
• PDB ID: 4L3T; 4NGE; 4RPU; 6XOS; 6XOT; 6XOU; 6XOV; 6XOW
• EC Number: 3.4.24.-
• Pfam ID: PF08367 ; PF00675 ; PF05193
• Sequence:
  MWRCGGRQGLCVLRRLSGGHAHHRAWRWNSNRACERALQYKLGDKIHGFTVNQVTSVPEL
  FLTAVKLTHDDTGARYLHLAREDTNNLFSVQFRTTPMDSTGVPHILEHTVLCGSQKYPCR
  DPFFKMLNRSLSTFMNAFTASDYTLYPFSTQNPKDFQNLLSVYLDATFFPCLRELDFWQE
  GWRLEHENPSDPQTPLVFKGVVFNEMKGAFTDNERIFSQHLQNRLLPDHTYSVVSGGDPL
  CIPELTWEQLKQFHATHYHPSNARFFTYGNFPLEQHLKQIHEEALSKFQKIEPSTVVPAQ
  TPWDKPREFQITCGPDSFATDPSKQTTISVSFLLPDITDTFEAFTLSLLSSLLTSGPNSP
  FYKALIESGLGTDFSPDVGYNGYTREAYFSVGLQGIAEKDIETVRSLIDRTIDEVVEKGF
  EDDRIEALLHKIEIQMKHQSTSFGLMLTSYIASCWNHDGDPVELLKLGNQLAKFRQCLQE
  NPKFLQEKVKQYFKNNQHKLTLSMRPDDKYHEKQAQVEATKLKQKVEALSPGDRQQIYEK
  GLELRSQQSKPQDASCLPALKVSDIEPTIPVTELDVVLTAGDIPVQYCAQPTNGMVYFRA
  FSSLNTLPEELRPYVPLFCSVLTKLGCGLLDYREQAQQIELKTGGMSASPHVLPDDSHMD
  TYEQGVLFSSLCLDRNLPDMMQLWSEIFNNPCFEEEEHFKVLVKMTAQELANGIPDSGHL
  YASIRAGRTLTPAGDLQETFSGMDQVRLMKRIAEMTDIKPILRKLPRIKKHLLNGDNMRC
  SVNATPQQMPQTEKAVEDFLRSIGRSKKERRPVRPHTVEKPVPSSSGGDAHVPHGSQVIR
  KLVMEPTFKPWQMKTHFLMPFPVNYVGECIRTVPYTDPDHASLKILARLMTAKFLHTEIR
  EKGGAYGGGAKLSHNGIFTLYSYRDPNTIETLQSFGKAVDWAKSGKFTQQDIDEAKLSVF
  STVDAPVAPSDKGMDHFLYGLSDEMKQAHREQLFAVSHDKLLAVSDRYLGTGKSTHGLAI
  LGPENPKIAKDPSWIIQ
• Function: Metalloendopeptidase of the mitochondrial matrix that functions in peptide cleavage and degradation rather than in protein processing. Has an ATP-independent activity. Specifically cleaves peptides in the range of 5 to 65 residues. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference. Degrades the transit peptides of mitochondrial proteins after their cleavage. Also degrades other unstructured peptides. It is also able to degrade amyloid-beta protein 40, one of the peptides produced by APP processing, when it accumulates in mitochondrion. It is a highly efficient protease, at least toward amyloid-beta protein 40. Cleaves that peptide at a specific position and is probably not processive, releasing digested peptides intermediates that can be further cleaved subsequently. It is also able to degrade amyloid-beta protein 42.
• Tissue Specificity: Widely expressed. Expressed at higher level in muscle and heart compared to brain, pancreas, liver, lung and placenta.
• Reactome Pathway: 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
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[2]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[3]
Spinocerebellar ataxia, autosomal recessive 30	DISW6SXV	Strong	Autosomal recessive	[3]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Presequence protease, mitochondrial (PITRM1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Presequence protease, mitochondrial (PITRM1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Presequence protease, mitochondrial (PITRM1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Presequence protease, mitochondrial (PITRM1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Presequence protease, mitochondrial (PITRM1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Presequence protease, mitochondrial (PITRM1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Presequence protease, mitochondrial (PITRM1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Presequence protease, mitochondrial (PITRM1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Presequence protease, mitochondrial (PITRM1).	[11]

References

• [1] Functional requirement for human pitrilysin metallopeptidase 1 arginine 183, mutated in amyloidogenic neuropathy.Protein Sci. 2018 Apr;27(4):861-873. doi: 10.1002/pro.3380. Epub 2018 Feb 23.
• [2] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [3] Defective PITRM1 mitochondrial peptidase is associated with A amyloidotic neurodegeneration. EMBO Mol Med. 2016 Mar 1;8(3):176-90. doi: 10.15252/emmm.201505894.
• [4] Reconstitution of Smad3 restores TGF-beta response of tissue inhibitor of metalloprotease-1 upregulation in human choriocarcinoma cells.Biochem Biophys Res Commun. 2003 Jan 10;300(2):383-90. doi: 10.1016/s0006-291x(02)02845-0.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [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] 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.