Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ57GGA)

• DOT Name: Ornithine transcarbamylase, mitochondrial (OTC)
• Synonyms: OTCase; EC 2.1.3.3; Ornithine carbamoyltransferase, mitochondrial
• Gene Name: OTC
• Related Disease: Ornithine transcarbamylase deficiency
• UniProt ID: OTC_HUMAN
• PDB ID: 1C9Y; 1EP9; 1FVO; 1OTH
• EC Number: 2.1.3.3
• Pfam ID: PF00185 ; PF02729
• Sequence:
  MLFNLRILLNNAAFRNGHNFMVRNFRCGQPLQNKVQLKGRDLLTLKNFTGEEIKYMLWLS
  ADLKFRIKQKGEYLPLLQGKSLGMIFEKRSTRTRLSTETGFALLGGHPCFLTTQDIHLGV
  NESLTDTARVLSSMADAVLARVYKQSDLDTLAKEASIPIINGLSDLYHPIQILADYLTLQ
  EHYSSLKGLTLSWIGDGNNILHSIMMSAAKFGMHLQAATPKGYEPDASVTKLAEQYAKEN
  GTKLLLTNDPLEAAHGGNVLITDTWISMGQEEEKKKRLQAFQGYQVTMKTAKVAASDWTF
  LHCLPRKPEEVDDEVFYSPRSLVFPEAENRKWTIMAVMVSLLTDYSPQLQKPKF
• Function: Catalyzes the second step of the urea cycle, the condensation of carbamoyl phosphate with L-ornithine to form L-citrulline. The urea cycle ensures the detoxification of ammonia by converting it to urea for excretion.
• Tissue Specificity: Mainly expressed in liver and intestinal mucosa.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Urea cycle (R-HSA-70635)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:HS00516-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ornithine transcarbamylase deficiency	DIS3DOIC	Definitive	X-linked	[1]

8 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 Ornithine transcarbamylase, mitochondrial (OTC).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Ornithine transcarbamylase, mitochondrial (OTC).	[7]

1 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 decreases the methylation of Ornithine transcarbamylase, mitochondrial (OTC).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paraquat	DMR8O3X	Investigative	Paraquat decreases the import of Ornithine transcarbamylase, mitochondrial (OTC).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [7] Sudden onset of ornithine carbamoyltransferase deficiency after aspirin ingestion. J Inherit Metab Dis. 1993;16(5):917. doi: 10.1007/BF00714301.
• [8] 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.
• [9] Oxidative stress inhibits the mitochondrial import of preproteins and leads to their degradation. Exp Cell Res. 2001 Feb 1;263(1):107-17. doi: 10.1006/excr.2000.5096.