Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF552H6)

• DOT Name: Cytochrome b5 reductase 4 (CYB5R4)
• Synonyms: EC 1.6.2.2; Flavohemoprotein b5/b5R; b5+b5R; N-terminal cytochrome b5 and cytochrome b5 oxidoreductase domain-containing protein; cb5/cb5R
• Gene Name: CYB5R4
• Related Disease:
  Maturity-onset diabetes of the young
  Non-insulin dependent diabetes
  Type-1/2 diabetes
• UniProt ID: NB5R4_HUMAN
• PDB ID: 3LF5; 6MV1; 6MV2
• EC Number: 1.6.2.2
• Pfam ID: PF04969 ; PF00173 ; PF00970 ; PF00175
• Sequence:
  MLNVPSQSFPAPRSQQRVASGGRSKVPLKQGRSLMDWIRLTKSGKDLTGLKGRLIEVTEE
  ELKKHNKKDDCWICIRGFVYNVSPYMEYHPGGEDELMRAAGSDGTELFDQVHRWVNYESM
  LKECLVGRMAIKPAVLKDYREEEKKVLNGMLPKSQVTDTLAKEGPSYPSYDWFQTDSLVT
  IAIYTKQKDINLDSIIVDHQNDSFRAETIIKDCLYLIHIGLSHEVQEDFSVRVVESVGKI
  EIVLQKKENTSWDFLGHPLKNHNSLIPRKDTGLYYRKCQLISKEDVTHDTRLFCLMLPPS
  THLQVPIGQHVYLKLPITGTEIVKPYTPVSGSLLSEFKEPVLPNNKYIYFLIKIYPTGLF
  TPELDRLQIGDFVSVSSPEGNFKISKFQELEDLFLLAAGTGFTPMVKILNYALTDIPSLR
  KVKLMFFNKTEDDIIWRSQLEKLAFKDKRLDVEFVLSAPISEWNGKQGHISPALLSEFLK
  RNLDKSKVLVCICGPVPFTEQGVRLLHDLNFSKNEIHSFTA
• Function: NADH-cytochrome b5 reductase involved in endoplasmic reticulum stress response pathway. Plays a critical role in protecting pancreatic beta-cells against oxidant stress, possibly by protecting the cell from excess buildup of reactive oxygen species (ROS). Reduces a variety of substrates in vitro, such as cytochrome c, feericyanide and methemoglobin.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Amino sugar and nucleotide sugar metabolism (hsa00520)
• Reactome Pathway: Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cytochrome b5 reductase 4 (CYB5R4).	[13]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Cytochrome b5 reductase 4 (CYB5R4).	[14]

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 Cytochrome b5 reductase 4 (CYB5R4).	[15]

References

• [1] Variation in NCB5OR: studies of relationships to type 2 diabetes, maturity-onset diabetes of the young, and gestational diabetes mellitus.Diabetes. 2004 Nov;53(11):2992-7. doi: 10.2337/diabetes.53.11.2992.
• [2] Absence of a reductase, NCB5OR, causes insulin-deficient diabetes.Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10750-5. doi: 10.1073/pnas.0404044101. Epub 2004 Jul 9.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] 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.
• [15] 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.