Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JRVY7)

• DOT Name: Metalloendopeptidase OMA1, mitochondrial (OMA1)
• Synonyms: EC 3.4.24.-; Metalloprotease-related protein 1; MPRP-1; Overlapping with the m-AAA protease 1 homolog
• Gene Name: OMA1
• Related Disease:
  Spinocerebellar ataxia type 37
  Advanced cancer
  Alzheimer disease
  Autosomal dominant optic atrophy, classic form
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac failure
  Cardiovascular disease
  Congestive heart failure
  Duane retraction syndrome
  Familial multiple trichoepithelioma
  Myocardial infarction
  Neoplasm
  Spinocerebellar ataxia type 28
  Autism
  Cognitive impairment
  Young-onset Parkinson disease
• UniProt ID: OMA1_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF01435
• Sequence:
  MSFICGLQSAARNHVFFRFNSLSNWRKCNTLASTSRGCHQVQVNHIVNKYQGLGVNQCDR
  WSFLPGNFHFYSTFNNKRTGGLSSTKSKEIWRITSKCTVWNDAFSRQLLIKEVTAVPSLS
  VLHPLSPASIRAIRNFHTSPRFQAAPVPLLLMILKPVQKLFAIIVGRGIRKWWQALPPNK
  KEVVKENIRKNKWKLFLGLSSFGLLFVVFYFTHLEVSPITGRSKLLLLGKEQFRLLSELE
  YEAWMEEFKNDMLTEKDARYLAVKEVLCHLIECNKDVPGISQINWVIHVVDSPIINAFVL
  PNGQMFVFTGFLNSVTDIHQLSFLLGHEIAHAVLGHAAEKAGMVHLLDFLGMIFLTMIWA
  ICPRDSLALLCQWIQSKLQEYMFNRPYSRKLEAEADKIGLLLAAKACADIRASSVFWQQM
  EFVDSLHGQPKMPEWLSTHPSHGNRVEYLDRLIPQALKIREMCNCPPLSNPDPRLLFKLS
  TKHFLEESEKEDLNITKKQKMDTLPIQKQEQIPLTYIVEKRTGS
• Function: Metalloprotease that is part of the quality control system in the inner membrane of mitochondria. Activated in response to various mitochondrial stress, leading to the proteolytic cleavage of target proteins, such as OPA1, UQCC3 and DELE1. Following stress conditions that induce loss of mitochondrial membrane potential, mediates cleavage of OPA1 at S1 position, leading to OPA1 inactivation and negative regulation of mitochondrial fusion. Also acts as a regulator of apoptosis: upon BAK and BAX aggregation, mediates cleavage of OPA1, leading to the remodeling of mitochondrial cristae and allowing the release of cytochrome c from mitochondrial cristae. In depolarized mitochondria, may also act as a backup protease for PINK1 by mediating PINK1 cleavage and promoting its subsequent degradation by the proteasome. May also cleave UQCC3 in response to mitochondrial depolarization. Also acts as an activator of the integrated stress response (ISR): in response to mitochondrial stress, mediates cleavage of DELE1 to generate the processed form of DELE1 (S-DELE1), which translocates to the cytosol and activates EIF2AK1/HRI to trigger the ISR. Its role in mitochondrial quality control is essential for regulating lipid metabolism as well as to maintain body temperature and energy expenditure under cold-stress conditions. Binds cardiolipin, possibly regulating its protein turnover. Required for the stability of the respiratory supercomplexes.
• Tissue Specificity: Widely expressed, with strong expression in the heart, skeletal muscle, kidney and liver.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Regulation of Apoptosis (R-HSA-169911)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 37	DIS3KNNO	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[4]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Duane retraction syndrome	DISOEBK2	Strong	Genetic Variation	[9]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[5]
Myocardial infarction	DIS655KI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Spinocerebellar ataxia type 28	DISL571D	Strong	Biomarker	[10]
Autism	DISV4V1Z	Limited	Altered Expression	[11]
Cognitive impairment	DISH2ERD	Limited	Altered Expression	[11]
Young-onset Parkinson disease	DIS05LFS	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[23]

14 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 Metalloendopeptidase OMA1, mitochondrial (OMA1).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[20]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[24]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[25]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Metalloendopeptidase OMA1, mitochondrial (OMA1).	[26]

References

• [1] Mutational mechanism for DAB1 (ATTTC)(n) insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.Hum Mutat. 2019 Apr;40(4):404-412. doi: 10.1002/humu.23704. Epub 2019 Jan 9.
• [2] Targeted OMA1 therapies for cancer.Int J Cancer. 2019 Nov 1;145(9):2330-2341. doi: 10.1002/ijc.32177. Epub 2019 Feb 21.
• [3] Understanding the interactions of different substrates with wild-type and mutant acylaminoacyl peptidase using molecular dynamics simulations.J Biomol Struct Dyn. 2018 Dec;36(16):4285-4302. doi: 10.1080/07391102.2017.1414634. Epub 2017 Dec 20.
• [4] Protective effect of hyperoside against renal ischemia-reperfusion injury via modulating mitochondrial fission, oxidative stress, and apoptosis.Free Radic Res. 2019 Jul;53(7):727-736. doi: 10.1080/10715762.2019.1623883. Epub 2019 Jun 11.
• [5] Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma.Carcinogenesis. 2013 Dec;34(12):2750-6. doi: 10.1093/carcin/bgt286. Epub 2013 Aug 29.
• [6] Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells.Sci Rep. 2019 Oct 14;9(1):14746. doi: 10.1038/s41598-019-49327-2.
• [7] Ablation of the stress protease OMA1 protects against heart failure in mice.Sci Transl Med. 2018 Mar 28;10(434):eaan4935. doi: 10.1126/scitranslmed.aan4935.
• [8] Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation.Cell Death Dis. 2018 May 1;9(5):556. doi: 10.1038/s41419-018-0579-9.
• [9] A peptidase gene in chromosome 8q is disrupted by a balanced translocation in a duane syndrome patient.Invest Ophthalmol Vis Sci. 2002 Dec;43(12):3609-12.
• [10] Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.J Med Genet. 2019 Aug;56(8):499-511. doi: 10.1136/jmedgenet-2018-105766. Epub 2019 Mar 25.
• [11] Reelin signaling is impaired in autism.Biol Psychiatry. 2005 Apr 1;57(7):777-87. doi: 10.1016/j.biopsych.2004.12.018.
• [12] Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.Mol Cell. 2019 Mar 7;73(5):1028-1043.e5. doi: 10.1016/j.molcel.2019.01.002. Epub 2019 Feb 4.
• [13] 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.
• [14] 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.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [18] 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.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [21] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] 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.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.