Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWIS44P)

• DOT Name: Mitochondrial ribonuclease P catalytic subunit (PRORP)
• Synonyms: EC 3.1.26.5; Mitochondrial ribonuclease P protein 3; Mitochondrial RNase P protein 3; Protein only RNase P catalytic subunit
• Gene Name: PRORP
• Related Disease:
  Juvenile idiopathic arthritis
  Rheumatoid arthritis
  Asthma
  Combined oxidative phosphorylation deficiency 54
  Coronary atherosclerosis
  Coronary heart disease
  Myocardial infarction
  Psoriasis
  Schizophrenia
• UniProt ID: MRPP3_HUMAN
• PDB ID: 4ROU; 4XGL; 4XGM; 7ONU
• EC Number: 3.1.26.5
• Pfam ID: PF16953
• Sequence:
  MTFYLFGIRSFPKLWKSPYLGLGPGHSYVSLFLADRCGIRNQQRLFSLKTMSPQNTKATN
  LIAKARYLRKDEGSNKQVYSVPHFFLAGAAKERSQMNSQTEDHALAPVRNTIQLPTQPLN
  SEEWDKLKEDLKENTGKTSFESWIISQMAGCHSSIDVAKSLLAWVAAKNNGIVSYDLLVK
  YLYLCVFHMQTSEVIDVFEIMKARYKTLEPRGYSLLIRGLIHSDRWREALLLLEDIKKVI
  TPSKKNYNDCIQGALLHQDVNTAWNLYQELLGHDIVPMLETLKAFFDFGKDIKDDNYSNK
  LLDILSYLRNNQLYPGESFAHSIKTWFESVPGKQWKGQFTTVRKSGQCSGCGKTIESIQL
  SPEEYECLKGKIMRDVIDGGDQYRKTTPQELKRFENFIKSRPPFDVVIDGLNVAKMFPKV
  RESQLLLNVVSQLAKRNLRLLVLGRKHMLRRSSQWSRDEMEEVQKQASCFFADDISEDDP
  FLLYATLHSGNHCRFITRDLMRDHKACLPDAKTQRLFFKWQQGHQLAIVNRFPGSKLTFQ
  RILSYDTVVQTTGDSWHIPYDEDLVERCSCEVPTKWLCLHQKT
• Function: Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends. The presence of TRMT10C/MRPP1, HSD17B10/MRPP2 is required to catalyze tRNA molecules in their 5'-ends.
• Reactome Pathway:
  tRNA modification in the mitochondrion (R-HSA-6787450)
  rRNA processing in the mitochondrion (R-HSA-8868766)
  tRNA processing in the mitochondrion (R-HSA-6785470)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Asthma	DISW9QNS	Limited	Genetic Variation	[3]
Combined oxidative phosphorylation deficiency 54	DIS0KCTN	Limited	Autosomal recessive	[4]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[5]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[5]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[5]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[7]

9 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 Mitochondrial ribonuclease P catalytic subunit (PRORP).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial ribonuclease P catalytic subunit (PRORP).	[16]

References

• [1] Identification of a novel candidate locus for juvenile idiopathic arthritis at 14q13.2 in the Latvian population by association analysis with microsatellite markers.DNA Cell Biol. 2010 Sep;29(9):543-51. doi: 10.1089/dna.2009.0970.
• [2] Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis.Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.
• [3] Genome-wide association study of leukotriene modifier response in asthma.Pharmacogenomics J. 2016 Apr;16(2):151-7. doi: 10.1038/tpj.2015.34. Epub 2015 Jun 2.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Haplotypes encompassing the KIAA0391 and PSMA6 gene cluster confer a genetic link for myocardial infarction and coronary artery disease.Ann Hum Genet. 2009 Sep;73(Pt 5):475-83. doi: 10.1111/j.1469-1809.2009.00534.x. Epub 2009 Jun 16.
• [6] Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.
• [7] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.