Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGSG868)

• DOT Name: Cytochrome b-245 heavy chain (CYBB)
• Synonyms: EC 1.-.-.-; CGD91-phox; Cytochrome b(558) subunit beta; Cytochrome b558 subunit beta; Heme-binding membrane glycoprotein gp91phox; NADPH oxidase 2; Neutrophil cytochrome b 91 kDa polypeptide; Superoxide-generating NADPH oxidase heavy chain subunit; gp91-1; gp91-phox; p22 phagocyte B-cytochrome
• Gene Name: CYBB
• Related Disease:
  Granulomatous disease, chronic, X-linked
  Chronic granulomatous disease
  X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency
• UniProt ID: CY24B_HUMAN
• PDB ID: 3A1F; 7U8G; 8GZ3
• EC Number: 1.-.-.-
• Pfam ID: PF08022 ; PF01794 ; PF08030
• Sequence:
  MGNWAVNEGLSIFVILVWLGLNVFLFVWYYRVYDIPPKFFYTRKLLGSALALARAPAACL
  NFNCMLILLPVCRNLLSFLRGSSACCSTRVRRQLDRNLTFHKMVAWMIALHSAIHTIAHL
  FNVEWCVNARVNNSDPYSVALSELGDRQNESYLNFARKRIKNPEGGLYLAVTLLAGITGV
  VITLCLILIITSSTKTIRRSYFEVFWYTHHLFVIFFIGLAIHGAERIVRGQTAESLAVHN
  ITVCEQKISEWGKIKECPIPQFAGNPPMTWKWIVGPMFLYLCERLVRFWRSQQKVVITKV
  VTHPFKTIELQMKKKGFKMEVGQYIFVKCPKVSKLEWHPFTLTSAPEEDFFSIHIRIVGD
  WTEGLFNACGCDKQEFQDAWKLPKIAVDGPFGTASEDVFSYEVVMLVGAGIGVTPFASIL
  KSVWYKYCNNATNLKLKKIYFYWLCRDTHAFEWFADLLQLLESQMQERNNAGFLSYNIYL
  TGWDESQANHFAVHHDEEKDVITGLKQKTLYGRPNWDNEFKTIASQHPNTRIGVFLCGPE
  ALAETLSKQSISNSESGPRGVHFIFNKENF
• Function: Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. It is the terminal component of a respiratory chain that transfers single electrons from cytoplasmic NADPH across the plasma membrane to molecular oxygen on the exterior. Also functions as a voltage-gated proton channel that mediates the H(+) currents of resting phagocytes. It participates in the regulation of cellular pH and is blocked by zinc.
• Tissue Specificity: Detected in neutrophils (at protein level).
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Phagosome (hsa04145)
  Ferroptosis (hsa04216)
  Necroptosis (hsa04217)
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Leukocyte transendothelial migration (hsa04670)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Alzheimer disease (hsa05010)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Leishmaniasis (hsa05140)
  Coro.virus disease - COVID-19 (hsa05171)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Cross-presentation of particulate exogenous antigens (phagosomes) (R-HSA-1236973)
  Detoxification of Reactive Oxygen Species (R-HSA-3299685)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Neutrophil degranulation (R-HSA-6798695)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  ROS and RNS production in phagocytes (R-HSA-1222556)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Granulomatous disease, chronic, X-linked	DISNTTS3	Definitive	X-linked	[1]
Chronic granulomatous disease	DIS9ZR24	Supportive	Autosomal recessive	[2]
X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency	DISZL6QU	Supportive	X-linked	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome b-245 heavy chain (CYBB).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome b-245 heavy chain (CYBB).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Cytochrome b-245 heavy chain (CYBB).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Cytochrome b-245 heavy chain (CYBB).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cytochrome b-245 heavy chain (CYBB).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Cytochrome b-245 heavy chain (CYBB).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Cytochrome b-245 heavy chain (CYBB).	[4]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of Cytochrome b-245 heavy chain (CYBB).	[10]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib increases the expression of Cytochrome b-245 heavy chain (CYBB).	[10]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Cytochrome b-245 heavy chain (CYBB).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cytochrome b-245 heavy chain (CYBB).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cytochrome b-245 heavy chain (CYBB).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cytochrome b-245 heavy chain (CYBB).	[9]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Cytochrome b-245 heavy chain (CYBB).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Cytochrome b-245 heavy chain (CYBB).	[15]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Cytochrome b-245 heavy chain (CYBB).	[16]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Cytochrome b-245 heavy chain (CYBB).	[17]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the expression of Cytochrome b-245 heavy chain (CYBB).	[18]
PATULIN	DM0RV9C	Investigative	PATULIN increases the expression of Cytochrome b-245 heavy chain (CYBB).	[19]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the expression of Cytochrome b-245 heavy chain (CYBB).	[20]
Eckol	DMIVY0Q	Investigative	Eckol decreases the expression of Cytochrome b-245 heavy chain (CYBB).	[21]

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 b-245 heavy chain (CYBB).	[12]

References

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• [10] Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
• [11] Dexamethasone but not indomethacin inhibits human phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity by down-regulating expression of genes encoding oxidase components. J Immunol. 1998 Nov 1;161(9):4960-7.
• [12] 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.
• [13] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [14] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [15] Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice. Biochem Biophys Res Commun. 2016 May 20;474(1):182-187. doi: 10.1016/j.bbrc.2016.04.097. Epub 2016 Apr 21.
• [16] Telmisartan Mitigates High-Glucose-Induced Injury in Renal Glomerular Endothelial Cells (rGECs) and Albuminuria in Diabetes Mice. Chem Res Toxicol. 2021 Sep 20;34(9):2079-2086. doi: 10.1021/acs.chemrestox.1c00159. Epub 2021 Aug 31.
• [17] Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells. Kidney Int. 2004 Dec;66(6):2329-36.
• [18] Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells. Neurotoxicology. 2022 Sep;92:166-179. doi: 10.1016/j.neuro.2022.08.007. Epub 2022 Aug 17.
• [19] Involvement of NADPH oxidase in patulin-induced oxidative damage and cytotoxicity in HEK293?cells. Food Chem Toxicol. 2021 Apr;150:112055. doi: 10.1016/j.fct.2021.112055. Epub 2021 Feb 9.
• [20] Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med. 2014 Aug;73:201-13. doi: 10.1016/j.freeradbiomed.2014.04.029. Epub 2014 May 14.
• [21] Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells. Toxicol Appl Pharmacol. 2011 Jul 1;254(1):32-40. doi: 10.1016/j.taap.2011.04.006. Epub 2011 Apr 14.