Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMHT3G6)

• DOT Name: Neutrophil cytosol factor 1 (NCF1)
• Synonyms: NCF-1; 47 kDa autosomal chronic granulomatous disease protein; 47 kDa neutrophil oxidase factor; NCF-47K; Neutrophil NADPH oxidase factor 1; Nox organizer 2; Nox-organizing protein 2; SH3 and PX domain-containing protein 1A; p47-phox
• Gene Name: NCF1
• Related Disease:
  Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1
  Chronic granulomatous disease
• UniProt ID: NCF1_HUMAN
• PDB ID: 1GD5; 1K4U; 1KQ6; 1NG2; 1O7K; 1OV3; 1UEC; 1W70; 1WLP; 7YXW
• Pfam ID: PF16621 ; PF08944 ; PF00787 ; PF00018
• Sequence:
  MGDTFIRHIALLGFEKRFVPSQHYVYMFLVKWQDLSEKVVYRRFTEIYEFHKTLKEMFPI
  EAGAINPENRIIPHLPAPKWFDGQRAAENRQGTLTEYCSTLMSLPTKISRCPHLLDFFKV
  RPDDLKLPTDNQTKKPETYLMPKDGKSTATDITGPIILQTYRAIANYEKTSGSEMALSTG
  DVVEVVEKSESGWWFCQMKAKRGWIPASFLEPLDSPDETEDPEPNYAGEPYVAIKAYTAV
  EGDEVSLLEGEAVEVIHKLLDGWWVIRKDDVTGYFPSMYLQKSGQDVSQAQRQIKRGAPP
  RRSSIRNAHSIHQRSRKRLSQDAYRRNSVRFLQQRRRQARPGPQSPGSPLEEERQTQRSK
  PQPAVPPRPSADLILNRCSESTKRKLASAV
• Function: NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
• Tissue Specificity: Detected in peripheral blood monocytes and neutrophils (at protein level).
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Phagosome (hsa04145)
  Osteoclast differentiation (hsa04380)
  Neutrophil extracellular trap formation (hsa04613)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Prion disease (hsa05020)
  Leishmaniasis (hsa05140)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• 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)
  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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	DISXUJ5S	Strong	Autosomal recessive	[1]
Chronic granulomatous disease	DIS9ZR24	Supportive	Autosomal recessive	[2]

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 Neutrophil cytosol factor 1 (NCF1).	[3]
Beta-D-Glucose	DM5IHYP	Investigative	Beta-D-Glucose increases the phosphorylation of Neutrophil cytosol factor 1 (NCF1).	[24]

22 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 Neutrophil cytosol factor 1 (NCF1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neutrophil cytosol factor 1 (NCF1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neutrophil cytosol factor 1 (NCF1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Neutrophil cytosol factor 1 (NCF1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Neutrophil cytosol factor 1 (NCF1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutrophil cytosol factor 1 (NCF1).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Neutrophil cytosol factor 1 (NCF1).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neutrophil cytosol factor 1 (NCF1).	[11]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Neutrophil cytosol factor 1 (NCF1).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Neutrophil cytosol factor 1 (NCF1).	[4]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Neutrophil cytosol factor 1 (NCF1).	[13]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Neutrophil cytosol factor 1 (NCF1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neutrophil cytosol factor 1 (NCF1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neutrophil cytosol factor 1 (NCF1).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Neutrophil cytosol factor 1 (NCF1).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Neutrophil cytosol factor 1 (NCF1).	[18]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Neutrophil cytosol factor 1 (NCF1).	[19]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Neutrophil cytosol factor 1 (NCF1).	[20]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Neutrophil cytosol factor 1 (NCF1).	[8]
PATULIN	DM0RV9C	Investigative	PATULIN increases the expression of Neutrophil cytosol factor 1 (NCF1).	[23]
Dimethylformamide	DML6O4N	Investigative	Dimethylformamide increases the expression of Neutrophil cytosol factor 1 (NCF1).	[26]
Oxalic Acid	DMLN2GQ	Investigative	Oxalic Acid increases the expression of Neutrophil cytosol factor 1 (NCF1).	[27]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
acrolein	DMAMCSR	Investigative	acrolein affects the metabolism of Neutrophil cytosol factor 1 (NCF1).	[21]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the localization of Neutrophil cytosol factor 1 (NCF1).	[22]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe affects the localization of Neutrophil cytosol factor 1 (NCF1).	[25]
2-Methylamino-succinic acid(NMDA)	DMKP6BM	Investigative	2-Methylamino-succinic acid(NMDA) affects the localization of Neutrophil cytosol factor 1 (NCF1).	[28]

References

• [1] Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease. Blood. 2000 Mar 15;95(6):2150-6.
• [2] Chronic Granulomatous Disease. 2012 Aug 9 [updated 2022 Apr 21]. 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] 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.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Effects of red grape juice polyphenols in NADPH oxidase subunit expression in human neutrophils and mononuclear blood cells. Br J Nutr. 2009 Oct;102(8):1125-35. doi: 10.1017/S0007114509382148. Epub 2009 May 19.
• [9] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [10] Ethanol directly induced HMGB1 release through NOX2/NLRP1 inflammasome in neuronal cells. Toxicology. 2015 Aug 6;334:104-10. doi: 10.1016/j.tox.2015.06.006. Epub 2015 Jun 12.
• [11] Nicotine stimulates CYP1A1 expression in human hepatocellular carcinoma cells via AP-1, NF-B, and AhR. Toxicol Lett. 2021 Oct 1;349:155-164. doi: 10.1016/j.toxlet.2021.06.013. Epub 2021 Jun 24.
• [12] Organochlorine pesticide-mediated induction of NADPH oxidase and nitric-oxide synthase in endothelial cell. J Clin Diagn Res. 2017 Jan;11(1):BC09-BC12.
• [13] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [14] 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.
• [15] Aryl hydrocarbon receptor-dependent induction of the NADPH oxidase subunit NCF1/p47 phox expression leading to priming of human macrophage oxidative burst. Free Radic Biol Med. 2009 Sep 15;47(6):825-34. doi: 10.1016/j.freeradbiomed.2009.06.025. Epub 2009 Jun 24.
• [16] Bisphenol A significantly enhances the neutrophilic differentiation of promyelocytic HL-60 cells. Int Immunopharmacol. 2003 Nov;3(12):1601-8. doi: 10.1016/S1567-5769(03)00182-6.
• [17] 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.
• [18] 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.
• [19] Evaluation of gliclazide ability to attenuate the hyperglycaemic 'memory' induced by high glucose in isolated human endothelial cells. Diabetes Metab Res Rev. 2008 May-Jun;24(4):301-9. doi: 10.1002/dmrr.804.
• [20] The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
• [21] Cigarette smoke impairs neutrophil respiratory burst activation by aldehyde-induced thiol modifications. Toxicology. 2001 Mar 7;160(1-3):207-17. doi: 10.1016/s0300-483x(00)00450-9.
• [22] Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. Atherosclerosis. 2010 Nov;213(1):225-34. doi: 10.1016/j.atherosclerosis.2010.08.056. Epub 2010 Aug 19.
• [23] 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.
• [24] Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67(phox) and p47(phox). J Biol Chem. 2002 Jul 12;277(28):25385-92. doi: 10.1074/jbc.M203630200. Epub 2002 May 6.
• [25] The anti-inflammatory effect of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol by targeting Lyn kinase in human neutrophils. Chem Biol Interact. 2015 Jul 5;236:90-101. doi: 10.1016/j.cbi.2015.05.004. Epub 2015 May 14.
• [26] TNF-related apoptosis-inducing ligand (TRAIL) is expressed throughout myeloid development, resulting in a broad distribution among neutrophil granules. J Leukoc Biol. 2008 Mar;83(3):621-9.
• [27] Anti-nephrolithic potential of resveratrol via inhibition of ROS, MCP-1, hyaluronan and osteopontin in vitro and in vivo. Pharmacol Rep. 2013;65(4):970-9.
• [28] Kukoamine B, an amide alkaloid, protects against NMDA-induced neurotoxicity and potential mechanisms in vitro. Neurochem Int. 2015 Aug;87:66-76. doi: 10.1016/j.neuint.2015.06.001. Epub 2015 Jun 9.