Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1CPE1K)

• DOT Name: Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3)
• Synonyms: EC 7.2.1.3; Cytochrome b ascorbate-dependent protein 3; Cytochrome b561 family member A3; Lysosomal cytochrome b; LCytb
• Gene Name: CYB561A3
• UniProt ID: CYAC3_HUMAN
• EC Number: 7.2.1.3
• Pfam ID: PF03188
• Sequence:
  MVSGRFYLSCLLLGSLGSMCILFTIYWMQYWRGGFAWNGSIYMFNWHPVLMVAGMVVFYG
  GASLVYRLPQSWVGPKLPWKLLHAALHLMAFVLTVVGLVAVFTFHNHGRTANLYSLHSWL
  GITTVFLFACQWFLGFAVFLLPWASMWLRSLLKPIHVFFGAAILSLSIASVISGINEKLF
  FSLKNTTRPYHSLPSEAVFANSTGMLVVAFGLLVLYILLASSWKRPEPGILTDRQPLLHD
  GE
• Function: Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce iron cations Fe(3+) into Fe(2+) in the lumen of the late endosome and lysosome. Reduced iron can then be extruded from the late endosome and lysosome to the cytoplasm by divalent metal-specific transporters. It is therefore most probably involved in endosomal and lysosomal cellular iron homeostasis.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[1]

7 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 Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[4]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[2]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysosomal membrane ascorbate-dependent ferrireductase CYB561A3 (CYB561A3).	[7]

References

• [1] 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.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] 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.