Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP9M7VW)

• DOT Name: Carbonic anhydrase 5A, mitochondrial (CA5A)
• Synonyms: EC 4.2.1.1; Carbonate dehydratase VA; Carbonic anhydrase VA; CA-VA
• Gene Name: CA5A
• Related Disease: Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
• UniProt ID: CAH5A_HUMAN
• EC Number: 4.2.1.1
• Pfam ID: PF00194
• Sequence:
  MLGRNTWKTSAFSFLVEQMWAPLWSRSMRPGRWCSQRSCAWQTSNNTLHPLWTVPVSVPG
  GTRQSPINIQWRDSVYDPQLKPLRVSYEAASCLYIWNTGYLFQVEFDDATEASGISGGPL
  ENHYRLKQFHFHWGAVNEGGSEHTVDGHAYPAELHLVHWNSVKYQNYKEAVVGENGLAVI
  GVFLKLGAHHQTLQRLVDILPEIKHKDARAAMRPFDPSTLLPTCWDYWTYAGSLTTPPLT
  ESVTWIIQKEPVEVAPSQLSAFRTLLFSALGEEEKMMVNNYRPLQPLMNRKVWASFQATN
  EGTRS
• Function: Mitochondrial carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate/HCO3. Mitochondria are impermeable to HCO3, and thus this intramitochondrial carbonic anhydrase is pivotal in providing HCO3 for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles.
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Reversible hydration of carbon dioxide (R-HSA-1475029)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency	DISJ7EE9	Definitive	Autosomal recessive	[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 Carbonic anhydrase 5A, mitochondrial (CA5A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[7]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Carbonic anhydrase 5A, mitochondrial (CA5A).	[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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.