Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3K93LZ)

• DOT Name: Carbonic anhydrase 4 (CA4)
• Synonyms: EC 4.2.1.1; Carbonate dehydratase IV; Carbonic anhydrase IV; CA-IV
• Gene Name: CA4
• Related Disease:
  Retinitis pigmentosa 17
  Retinitis pigmentosa
• UniProt ID: CAH4_HUMAN
• PDB ID: 1ZNC; 3F7B; 3F7U; 3FW3; 5IPZ; 5JN8; 5JN9; 5JNA; 5JNC; 5KU6
• EC Number: 4.2.1.1
• Pfam ID: PF00194
• Sequence:
  MRMLLALLALSAARPSASAESHWCYEVQAESSNYPCLVPVKWGGNCQKDRQSPINIVTTK
  AKVDKKLGRFFFSGYDKKQTWTVQNNGHSVMMLLENKASISGGGLPAPYQAKQLHLHWSD
  LPYKGSEHSLDGEHFAMEMHIVHEKEKGTSRNVKEAQDPEDEIAVLAFLVEAGTQVNEGF
  QPLVEALSNIPKPEMSTTMAESSLLDLLPKEEKLRHYFRYLGSLTTPTCDEKVVWTVFRE
  PIQLHREQILAFSQKLYYDKEQTVSMKDNVRPLQQLGQRTVIKSGAPGRPLPWALPALLG
  PMLACLLAGFLR
• Function: Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.
• Tissue Specificity: Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels.
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
  Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway:
  Erythrocytes take up oxygen and release carbon dioxide (R-HSA-1247673)
  Reversible hydration of carbon dioxide (R-HSA-1475029)
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 17	DIS7LCIM	Strong	Autosomal dominant	[1]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]

12 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 4 (CA4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbonic anhydrase 4 (CA4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Carbonic anhydrase 4 (CA4).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Carbonic anhydrase 4 (CA4).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Carbonic anhydrase 4 (CA4).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Carbonic anhydrase 4 (CA4).	[6]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Carbonic anhydrase 4 (CA4).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbonic anhydrase 4 (CA4).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Carbonic anhydrase 4 (CA4).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Carbonic anhydrase 4 (CA4).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Carbonic anhydrase 4 (CA4).	[11]
Sulfate	DMW0ZBF	Investigative	Sulfate decreases the activity of Carbonic anhydrase 4 (CA4).	[12]

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 affects the methylation of Carbonic anhydrase 4 (CA4).	[9]

References

• [1] Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6617-22. doi: 10.1073/pnas.0401529101. Epub 2004 Apr 16.
• [2] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] 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.
• [7] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [12] Carbonic anhydrase inhibitorsInhibition of isozymes I, II, IV, V, and IX with anions isosteric and isoelectronic with sulfate, nitrate, and carbonate. Bioorg Med Chem Lett. 2005 Feb 1;15(3):567-71.