Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61GMNV)

• DOT Name: Transmembrane ascorbate-dependent reductase CYB561 (CYB561)
• Synonyms: EC 7.2.1.-; Cytochrome b-561; Cytochrome b561
• Gene Name: CYB561
• Related Disease:
  Orthostatic hypotension
  Adult glioblastoma
  Depression
  Glioblastoma multiforme
  Orthostatic hypotension 2
• UniProt ID: CY561_HUMAN
• EC Number: 7.2.1.-
• Pfam ID: PF03188
• Sequence:
  MEGGAAAATPTALPYYVAFSQLLGLTLVAMTGAWLGLYRGGIAWESDLQFNAHPLCMVIG
  LIFLQGNALLVYRVFRNEAKRTTKVLHGLLHIFALVIALVGLVAVFDYHRKKGYADLYSL
  HSWCGILVFVLYFVQWLVGFSFFLFPGASFSLRSRYRPQHIFFGATIFLLSVGTALLGLK
  EALLFNLGGKYSAFEPEGVLANVLGLLLACFGGAVLYILTRADWKRPSQAEEQALSMDFK
  TLTEGDSPGSQ
• Function: Transmembrane reductase that uses ascorbate as an electron donor in the cytoplasm and transfers electrons across membranes to reduce monodehydro-L-ascorbate radical in the lumen of secretory vesicles. It is therefore involved the regeneration and homeostasis within secretory vesicles of ascorbate which in turn provides reducing equivalents needed to support the activity of intravesicular enzymes.
• Tissue Specificity: Expressed in many tissues, in particular the brain especially in the cortex and hippocampus.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Orthostatic hypotension	DISBKQGT	Definitive	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Depression	DIS3XJ69	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Orthostatic hypotension 2	DISS8H0X	Limited	Autosomal recessive	[4]

2 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 Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[16]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Transmembrane ascorbate-dependent reductase CYB561 (CYB561).	[18]

References

• [1] Congenital absence of norepinephrine due to CYB561 mutations.Neurology. 2020 Jan 14;94(2):e200-e204. doi: 10.1212/WNL.0000000000008734. Epub 2019 Dec 10.
• [2] Mouse cytochrome b561: cDNA cloning and expression in rat brain, mouse embryos, and human glioma cell lines.DNA Cell Biol. 1998 Sep;17(9):771-7. doi: 10.1089/dna.1998.17.771.
• [3] Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus.Transl Psychiatry. 2018 Sep 7;8(1):187. doi: 10.1038/s41398-018-0240-5.
• [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] 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.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Inorganic arsenic as an endocrine disruptor: modulation of the glucocorticoid receptor pathway in placental cells via CpG methylation. Chem Res Toxicol. 2019 Mar 18;32(3):493-499.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] 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.