NOX5

Summary

NOX5 (NADPH oxidase 5, HGNC:14874) is a protein-coding gene on chromosome 15q23, encoding NADPH oxidase 5 (Q96PH1). Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor.

Enables proton channel activity and superoxide-generating NAD(P)H oxidase activity. Involved in several processes, including endothelial cell proliferation; proton transmembrane transport; and superoxide anion generation. Located in endoplasmic reticulum and plasma membrane.

Source: NCBI Gene 79400 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 122 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_024505

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14874
Approved symbol	NOX5
Name	NADPH oxidase 5
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	NOX5A, NOX5B
Ensembl gene	ENSG00000255346
Ensembl biotype	protein_coding
OMIM	606572
Entrez	79400

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000388866, ENST00000525143, ENST00000525163, ENST00000527315, ENST00000529367, ENST00000530406

RefSeq mRNA: 2 — MANE Select: NM_024505 NM_001184779, NM_024505

CCDS: CCDS32276, CCDS53954

Canonical transcript exons

ENST00000388866 — 16 exons

Exon	Start	End
ENSE00001419457	69014695	69014785
ENSE00001825381	69056565	69062762
ENSE00002729824	69028215	69028365
ENSE00003464941	69033043	69033277
ENSE00003513097	69047413	69047537
ENSE00003515533	69048959	69049058
ENSE00003521263	69047830	69047911
ENSE00003521349	69037028	69037210
ENSE00003534301	69055334	69055500
ENSE00003540315	69035354	69035507
ENSE00003540443	69042663	69042805
ENSE00003581544	69038857	69038989
ENSE00003590142	69046822	69046866
ENSE00003624531	69035758	69035936
ENSE00003646349	69026528	69026651
ENSE00004473629	69031518	69031812

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 95.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2987 / max 108.9009, expressed in 48 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147424	2.7570	851
147427	0.1867	40
147429	0.0815	6
147428	0.0304	22

Top tissues by expression

269 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	95.49	gold quality
type B pancreatic cell	CL:0000169	94.93	gold quality
diaphragm	UBERON:0001103	92.89	gold quality
left ventricle myocardium	UBERON:0006566	89.15	gold quality
tongue squamous epithelium	UBERON:0006919	87.93	gold quality
CA1 field of hippocampus	UBERON:0003881	86.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.80	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.66	gold quality
inferior olivary complex	UBERON:0002127	86.48	gold quality
triceps brachii	UBERON:0001509	86.18	gold quality
myocardium	UBERON:0002349	85.78	gold quality
cervix squamous epithelium	UBERON:0006922	85.14	gold quality
gluteal muscle	UBERON:0002000	84.57	silver quality
vastus lateralis	UBERON:0001379	84.50	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	84.43	gold quality
mucosa of urinary bladder	UBERON:0001259	84.24	gold quality
quadriceps femoris	UBERON:0001377	83.44	gold quality
epithelial cell of pancreas	CL:0000083	83.12	gold quality
oocyte	CL:0000023	82.20	gold quality
nasal cavity epithelium	UBERON:0005384	82.15	gold quality
cervix epithelium	UBERON:0004801	81.81	gold quality
parotid gland	UBERON:0001831	81.45	gold quality
orbitofrontal cortex	UBERON:0004167	81.45	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.19	gold quality
thymus	UBERON:0002370	80.88	silver quality
vena cava	UBERON:0004087	80.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	78.95	gold quality
biceps brachii	UBERON:0001507	78.54	gold quality
upper arm skin	UBERON:0004263	78.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, JUN, NFKB1, RELA, STAT1, STAT3, STAT5A

miRNA regulators (miRDB)

35 targeting NOX5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-331-3P	98.76	64.91	793

Literature-anchored findings (GeneRIF, showing 40)

• NOX5 is likely to be involved in Ca(2+)-activated, redox-dependent processes of spermatozoa and lymphocytes such as sperm-oocyte fusion, cell proliferation, and cytokine secretion. (PMID:11483596)
• Reactive oxygen species producing activity of NOX5 in sperm and NADPH-oxidase of white blood cells; role of protein kinase C in NOX5 activation (PMID:12121572)
• we propose that the GTP-bound active form of Rac is required for sustained enzyme activity and that membrane-localized GAPs have a role in the deactivation of NADPH oxidase (PMID:12186557)
• the regulatory N terminus and the catalytic C terminus of NOX5 interact in a Ca(2+)-dependent way; enzyme activation occurs through an intra-molecular interaction (PMID:14982937)
• Appreciable bacterial phospholipid degradation occurs only in the presence of catalytically active group IIA-phospholipase A2 and a functional respiratory burst NADPH oxidase in neutrophils. (PMID:16177112)
• Hairy cells(but not circulating normal B cells or some other lymphoid cell types) express NOX5; the inactivation of SHP-1 by NOX5-generated ROS contributes to the maintenance of the constitutive activation of HCs. (PMID:16339585)
• Knockdown of NOX5 also significantly decreased retinoblastoma protein phosphorylation and increased cell apoptosis and caspase-9 expression. (PMID:16707484)
• NO-mediated down-regulation by shear stress preferentially affects the gp91(phox)/p47(phox)-containing NAD(P)H oxidase complex. (PMID:16873416)
• Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations of one of the subunits of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to decreased of neutrophil oxidative burst. (PMID:17089090)
• NADPH oxidase is involved in the superoxide release by RA synovial cells, constitutively and after cytokine up-regulation. (PMID:17122966)
• phosphorylation of Nox5 at key residues facilitates enzyme activation at lower levels of intracellular calcium and may provide an avenue for enzyme activation in response to a greater variety of extracellular stimuli (PMID:17164239)
• NAD(P)H oxidase polymorphism (C242T) associates with recurrent coronary events in postinfarction patients (PMID:17214994)
• calmodulin binds to the NOX5 C terminus consensus calmodulin-binding domain in a Ca(2+)-dependent manner, changes its conformation and increases the Ca(2+) sensitivity of the N terminus-regulated enzymatic activity. (PMID:17346712)
• Results demonstrate that NOX5 can be found intracellularly and at the cell surface. (PMID:17587483)
• Inhibition of NADPH oxidase by apocynin may represent an attractive therapeutic approach to treat heart failure. (PMID:17603936)
• Acid-induced NOX5-S expression is mediated by platelet activating factor and STAT5 in esophageal adenocarcinoma cells. (PMID:17947454)
• ROS produced by Nox5 play an important role in platelet-derived growth factor-induced JAK/STAT activation and human aortic smooth muscle cell proliferation (PMID:18466778)
• NADPH oxidase activation is required for rhLIGHT-induced migration in human monocytes. (PMID:18468509)
• extracellular ROS production by Nox5 is modulated by PtdIns(4,5)P(2) by localizing Nox5 to the plasma membrane (PMID:18614798)
• In vitro NADPH oxidase activity assay reveals that this glycine mutant of the full-length protein greatly reduced NADPH oxidase activity upon activation even though it displayed PI(3,4)P2 binding activity comparable to that of the isolated PX domain. (PMID:18672905)
• Data show that bile acid reflux present in patients with BE may increase reactive oxygen species production and cell proliferation via activation of PI-PLCgamma2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA. (PMID:20086178)
• Shingosylphosphorylcholine down-regulates FLG gene transcription through NOX5-based NADPH oxidase and COX-2 in human keratinocytes. (PMID:20230798)
• Endothelial cells possess functionally active Nox5 that is regulated at the transcriptional/translational levels by Ang II and ET-1 through calcium/calmodulin-sensitive processes. (PMID:20339118)
• The effect of pH on the expression of p16 and NOX5-S on Barrett’s esophagus cells and their progression to esophageal adenocarcinoma are reported. (PMID:20576920)
• The current work is the first to demonstrate that MAPK signaling can directly influence the phosphorylation state of transmembrane NOX5 enzyme, contributing to NOX5’s activation in response to phorbol 12-myristate acetate and at resting calcium levels. (PMID:21297032)
• Nox5 forms a catalytically active oligomer in the membrane that is mediated by its dehydrogenase domain (PMID:21319793)
• Rac1 may be important in activation of NOX5-S in Barrett’s esphageal adenocarcinoma cells. (PMID:21525435)
• Reduced matrigel invasion was mediated by reduced ROS levels coinciding with decreased expression of NADPH oxidase 2, 3, 4 and 5 involved in ROS production. (PMID:21901141)
• There has been a rapid increase in our understanding of the NOX5 gene, the structural and biochemical aspects of the NOX5 enzyme, the role NOX5 plays in health and disease, and the development of novel NOX inhibitors. [Review] (PMID:22182486)
• Inhibition of NOX5 activity reduces spermatozoa motility. (PMID:22291013)
• results suggest that endogenously produced NO can directly S-nitrosylate and inhibit the activity of Nox5 (PMID:22387196)
• Nox5-alpha and -beta splice variants are the major isoforms that are expressed blood vessels and the only variants capable of ROS production. (PMID:22427510)
• we demonstrate NOX5 expression in human intramyocardial blood vessels and cardiomyocytes, with significant increases in the affected myocardium after acute myocardial infarction. (PMID:22503554)
• this study demonstrates the presence of NOX5 in acrosomal, equatorial, post-acrosomal regions, the body and the tail of ejaculated human teratozoospermia. (PMID:23030296)
• Overexpression of NOX5-S significantly increased the luciferase activity. (PMID:23439561)
• Tissue microarray analysis revealed, for the first time, substantial Nox5 overexpression in several human cancers (PMID:23851018)
• podocyte Nox5 has an important role in impaired renal function and hypertension. (PMID:24262797)
• The study reveals that PKC-alpha is the primary isoform mediating the activation of Nox5. (PMID:24505490)
• Results show that NOX5 is expressed in human renal proximal tubule cells and to greater extent than the other NOX isoforms in hypertensive than normotensive subjects. (PMID:24688893)
• Initial findings suggest that glomerular and tubular expression of Nox5 is induced during diabetes and hypertension, respectively. Furthermore, identification of SNPs in distinct human populations suggests a role for either good or ill for this enzyme. (PMID:25415612)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	nox5	ENSDARG00000079773
drosophila_melanogaster	Nox	FBGN0085428

Paralogs (6): NOX1 (ENSG00000007952), NOX3 (ENSG00000074771), NOX4 (ENSG00000086991), DUOX1 (ENSG00000137857), DUOX2 (ENSG00000140279), CYBB (ENSG00000165168)

Protein

Protein identifiers

NADPH oxidase 5 — Q96PH1 (reviewed: Q96PH1)

All UniProt accessions (2): A0A0B4J289, Q96PH1

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. Also synthesizes NAADP from its reduced NAADPH form which promotes Ca(2+) signaling during T cell activation. May play a role in cell growth and apoptosis. Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. Involved in endothelial generation of reactive oxygen species (ROS), proliferation and angiogenesis and contributes to endothelial response to thrombin. Regulates redox-dependent processes in lymphocytes and spermatozoa. Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. This isoform lacks calcium-binding domains and was showed to present a NADPH oxidase activity in a calcium-independent manner. May be involved in endothelial generation of reactive oxygen species (ROS), proliferation and angiogenesis and contribute to endothelial response to thrombin. However another study showed an absence of oxidase activity. Subject to rapid degradation. Lacks calcium-dependent NADPH oxidase activity. Lacks calcium-dependent NADPH oxidase activity.

Subunit / interactions. Homooligomer.

Subcellular location. Endoplasmic reticulum. Cell membrane Endoplasmic reticulum.

Tissue specificity. Mainly expressed in pachytene spermatocytes of testis and in lymphocyte-rich areas of spleen and lymph nodes. Also detected in ovary, placenta, pancreas, cardiac fibroblasts. Expressed in B-cells and prostate malignant cells. Expressed in spleen. Expressed in endothelial cells, pulmonary artery smooth muscle cells and epithelial colorectal adenocarcinoma cells. Expressed in microvascular endothelial cells (at protein level). Expressed in testis. Expressed in endothelial cells and pulmonary artery smooth muscle cells. Expressed in pulmonary artery smooth muscle cells and epithelial colorectal adenocarcinoma cells. Expressed in endothelial cells and pulmonary artery smooth muscle cells. Expressed in microvascular endothelial cells (at protein level).

Post-translational modifications. Phosphorylation at Ser-475 by CaMK2 and at Ser-490, Thr-494 and Ser-498 by PKC/PRKCA positively regulates its catalytic activity. S-nitrosylation in response to nitric oxide inhibits its catalytic activity.

Activity regulation. Activated by calcium which induces conformational changes and interaction between the N-terminal regulatory region and the C-terminal catalytic region. Inhibited by diphenylene iodonium.

Domain organisation. The C-lobe of the N-terminal calmodulin-like regulatory EF-domain acquires a folded and ordered structure upon calcium binding, and as a consequence, it is able to bind the C-terminal catalytic dehydrogenase domain, triggering enzyme activation. The C-terminal catalytic dehydrogenase domain mediates its homooligomerization. Absence of enzyme activity may be because the third EF-hand domain is interrupted by an insert. Absence of enzyme activity may be because the third EF-hand domain is interrupted by an insert. Absence of enzyme activity may be due to absence of EF-hand domains.

Induction. Down-regulated by TGFB1.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96PH1-1	v3, NOX5gamma	yes
Q96PH1-3	v1, NOX5alpha
Q96PH1-4	v2, NOX5beta
Q96PH1-2	v4, NOX5delta
Q96PH1-5	v5, NOX5epsilon, NOX5S
Q96PH1-6	v6, NOX5zeta

RefSeq proteins (2): NP_001171708, NP_078781* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013112	FAD-bd_8	Domain
IPR013121	Fe_red_NAD-bd_6	Domain
IPR013130	Fe3_Rdtase_TM_dom	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR050369	RBOH/FRE	Family

Pfam: PF01794, PF08022, PF08030, PF13202, PF13405

Catalyzed reactions (Rhea), 2 shown:

• NADPH + 2 O2 = 2 superoxide + NADP(+) + H(+) (RHEA:63180)
• NAADPH + 2 O2 = NAADP(+) + 2 superoxide + H(+) (RHEA:86239)

UniProt features (139 total): helix 28, mutagenesis site 21, strand 17, binding site 17, modified residue 10, topological domain 8, turn 8, transmembrane region 7, region of interest 6, domain 6, splice variant 4, sequence conflict 4, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6SZ5	X-RAY DIFFRACTION	2.23
8U85	ELECTRON MICROSCOPY	3.2
8U86	ELECTRON MICROSCOPY	3.3
8U87	ELECTRON MICROSCOPY	3.86
8U7Y	ELECTRON MICROSCOPY	4.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PH1-F1	80.89	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (17): 42; 44; 49; 70; 72; 74; 76; 81; 106; 108; 138; 140 …

Post-translational modifications (10): 107, 246, 475, 490, 494, 498, 502, 519, 659, 694

Mutagenesis-validated functional residues (21):

Position	Phenotype
277	loss of activity but no effect on protein levels.
567	loss of activity but no effect on protein levels.
656	loss of activity but no effect on protein levels.
31	loss of binding of 1 calcium molecule. no effect on catalytic activity.
107	substantial loss of catalytic activity.
110	no effect on cell membrane localization and catalytic activity.
111	no effect on cell membrane localization and catalytic activity.
112	no effect on cell membrane localization and catalytic activity.
113	significant reduction in cell membrane localization and catalytic activity. reduced calcium-dependent interaction betwee
114	no effect on cell membrane localization and catalytic activity.
115	significant reduction in cell membrane localization and catalytic activity. no effect on calcium-dependent interaction b
116	no effect on cell membrane localization and catalytic activity.
475	loss of camk2-mediated activation of its activity.
490	loss of pkc/prkca-mediated activation of its activity; when associated with a-494 and a-498.
494	no effect on camk2-mediated activation of its activity. loss of pkc/prkca-mediated activation of its activity; when asso
498	no effect on camk2-mediated activation of its activity. loss of pkc/prkca-mediated activation of its activity; when asso
502	no effect on camk2-mediated activation of its activity.
519	very significant loss of catalytic activity.
549	no effect on cell membrane localization but loss of catalytic activity.
659	no effect on camk2-mediated activation of its activity.
694	reduced nitrosylation. very significant loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3299685	Detoxification of Reactive Oxygen Species

MSigDB gene sets: 97 (showing top): GOBP_SINGLE_FERTILIZATION, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_MONOATOMIC_CATION_TRANSPORT, ONKEN_UVEAL_MELANOMA_UP, GOBP_CYTOKINESIS, GOBP_CYTOKINE_PRODUCTION, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM

GO Biological Process (12): angiogenesis (GO:0001525), positive regulation of cytokine production (GO:0001819), endothelial cell proliferation (GO:0001935), apoptotic process (GO:0006915), defense response (GO:0006952), superoxide anion generation (GO:0042554), regulation of fusion of sperm to egg plasma membrane (GO:0043012), cytoskeleton-dependent cytokinesis (GO:0061640), proton transmembrane transport (GO:1902600), positive regulation of reactive oxygen species metabolic process (GO:2000379), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (10): calcium ion binding (GO:0005509), proton channel activity (GO:0015252), superoxide-generating NAD(P)H oxidase activity (GO:0016175), heme binding (GO:0020037), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), superoxide-generating NADPH oxidase activity (GO:0106292), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor (GO:0050664)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), NADPH oxidase complex (GO:0043020), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
epithelial cell proliferation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to stress	1
superoxide metabolic process	1
fusion of sperm to egg plasma membrane involved in single fertilization	1
regulation of cellular process	1
regulation of multicellular organismal process	1
regulation of reproductive process	1
cytokinesis	1
monoatomic cation transmembrane transport	1
positive regulation of metabolic process	1
reactive oxygen species metabolic process	1
regulation of reactive oxygen species metabolic process	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
metal ion binding	1
monoatomic cation channel activity	1
proton transmembrane transporter activity	1
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	1
tetrapyrrole binding	1
nucleotide binding	1
anion binding	1
adenyl nucleotide binding	1
superoxide-generating NAD(P)H oxidase activity	1
catalytic activity	1
cation binding	1
oxidoreductase activity, acting on NAD(P)H	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1

Protein interactions and networks

STRING

990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOX5	CYBA	P13498	989
NOX5	NOX4	Q9NPH5	989
NOX5	CYBB	P04839	987
NOX5	NOX3	Q9HBY0	986
NOX5	NOX1	Q9Y5S8	986
NOX5	DUOX1	Q9NRD9	984
NOX5	NCF1	P14598	946
NOX5	NCF2	P19878	937
NOX5	NCF4	Q15080	860
NOX5	DUOX2	Q9NRD8	828
NOX5	NOXA1	Q86UR1	808
NOX5	NOXO1	Q8NFA2	793
NOX5	CD22	P20273	747
NOX5	POLDIP2	Q9Y2S7	681
NOX5	AKT1	P31749	677

IntAct

2 interactions, top by confidence:

A	B	Type	Score
NOX5	RNASEH2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): NOX5 (Biochemical Activity), MTHFR (Affinity Capture-MS), GUCY1B3 (Affinity Capture-MS), PDP2 (Affinity Capture-MS), TTC4 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), PRKAR1B (Affinity Capture-MS), STIP1 (Affinity Capture-MS), DDRGK1 (Affinity Capture-MS), NOX5 (Reconstituted Complex), NOX5 (Affinity Capture-Western), GUCY1B3 (Affinity Capture-MS), TTC4 (Affinity Capture-MS), PRKAR1B (Affinity Capture-MS), PDP2 (Affinity Capture-MS)

ESM2 similar proteins: A2AE42, A3A9H6, A5D7C9, A5D9A7, A6NM10, B3SHH9, B5DFH9, B9EJG8, F1NZP5, O14569, P10897, P49447, P82352, Q08DE1, Q14714, Q148G2, Q3ZCD2, Q5E965, Q5ND56, Q5RCZ2, Q5U2W7, Q5ZJX0, Q60720, Q62147, Q641Y1, Q6GPL4, Q6P0C6, Q6P1H1, Q71RH2, Q7TNV1, Q80ZE4, Q86TG1, Q8BMD6, Q8C8S3, Q8IXF9, Q8N8Q1, Q8NBI2, Q8TBR7, Q8VHW3, Q8VHW7

Diamond homologs: A0AAR7, B3VSB7, B5FZ84, G5EDN6, O81223, O81445, P0CM54, P0CM55, P25296, P28470, P29104, P29105, P34057, P35243, P35332, P36608, P37235, P42322, P42324, P42325, P62166, P62167, P62168, P62748, P62749, P63098, P63099, P63100, P84074, P84075, P84076, P87072, Q06AT0, Q06AT1, Q16982, Q28IM6, Q2TBI5, Q2V8Y7, Q38873, Q3HRN7

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	NOX5	phosphorylation
PRKCA	up-regulates	NOX5	phosphorylation
NOX5	up-regulates	ROS
NOX5	“up-regulates quantity”	superoxide	“chemical modification”
ABL1	“up-regulates activity”	NOX5	phosphorylation
CAMK2A	“up-regulates activity”	NOX5	phosphorylation
CAMK2A	unknown	NOX5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

122 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	110
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3387 predictions. Top by Δscore:

Variant	Effect	Δscore
15:69014782:GAGG:G	donor_gain	1.0000
15:69014784:GG:G	donor_gain	1.0000
15:69014785:GG:G	donor_gain	1.0000
15:69026526:A:AG	acceptor_gain	1.0000
15:69026527:G:GG	acceptor_gain	1.0000
15:69031811:AGG:A	donor_loss	1.0000
15:69031812:GGTAC:G	donor_loss	1.0000
15:69031813:G:C	donor_loss	1.0000
15:69031814:T:G	donor_loss	1.0000
15:69033274:CGCGG:C	donor_loss	1.0000
15:69033275:GCG:G	donor_gain	1.0000
15:69033278:GTAG:G	donor_loss	1.0000
15:69033279:T:A	donor_loss	1.0000
15:69035504:TTTGG:T	donor_loss	1.0000
15:69035506:TGGT:T	donor_loss	1.0000
15:69035508:G:A	donor_loss	1.0000
15:69035509:T:G	donor_loss	1.0000
15:69035510:GAGT:G	donor_loss	1.0000
15:69037187:G:GT	donor_gain	1.0000
15:69037187:G:T	donor_gain	1.0000
15:69047411:A:AG	acceptor_gain	1.0000
15:69047412:G:GG	acceptor_gain	1.0000
15:69047826:TCA:T	acceptor_loss	1.0000
15:69047827:CA:C	acceptor_loss	1.0000
15:69047828:A:AG	acceptor_gain	1.0000
15:69047828:A:AT	acceptor_loss	1.0000
15:69047828:AG:A	acceptor_gain	1.0000
15:69047829:G:GA	acceptor_gain	1.0000
15:69047829:GG:G	acceptor_gain	1.0000
15:69047829:GGC:G	acceptor_gain	1.0000

AlphaMissense

5036 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:69038968:A:C	S495R	0.999
15:69038970:C:A	S495R	0.999
15:69038970:C:G	S495R	0.999
15:69048971:T:A	W638R	0.999
15:69048971:T:C	W638R	0.999
15:69049001:T:A	W648R	0.999
15:69049001:T:C	W648R	0.999
15:69047495:G:A	G592D	0.998
15:69047477:T:C	L586P	0.997
15:69047482:G:T	G588W	0.997
15:69047483:G:A	G588E	0.997
15:69055492:T:A	W720R	0.997
15:69055492:T:C	W720R	0.997
15:69038867:T:C	L461P	0.996
15:69047477:T:A	L586H	0.996
15:69047519:T:C	L600P	0.996
15:69049003:G:C	W648C	0.996
15:69049003:G:T	W648C	0.996
15:69055460:T:C	L709P	0.996
15:69038953:C:G	H490D	0.995
15:69038959:T:C	F492L	0.995
15:69038961:C:A	F492L	0.995
15:69038961:C:G	F492L	0.995
15:69038971:A:C	S496R	0.995
15:69038973:T:A	S496R	0.995
15:69038973:T:G	S496R	0.995
15:69042698:T:A	W514R	0.995
15:69042698:T:C	W514R	0.995
15:69047510:C:A	A597D	0.995
15:69055444:G:C	D704H	0.995

dbSNP variants (sampled 300 via entrez): RS1000025783 (15:68958160 G>A,T), RS1000033058 (15:69062427 C>T), RS1000057724 (15:69018588 G>A,C), RS1000107522 (15:68944899 ACT>A), RS1000109545 (15:69018267 C>A,T), RS1000109715 (15:69009654 A>G), RS1000132071 (15:68939082 G>A), RS1000145988 (15:68929681 T>C), RS1000156278 (15:68975975 G>A,C), RS1000194994 (15:69047043 A>G,T), RS1000205883 (15:68993232 G>A), RS1000233748 (15:69016094 G>A), RS1000237572 (15:69045245 A>G), RS1000311029 (15:69046682 C>A,T), RS1000313518 (15:69002410 A>G)

Disease associations

OMIM: gene MIM:606572 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001726_6	Lipoprotein-associated phospholipase A2 activity change in response to statin therapy	2.000000e-06
GCST001762_264	Obesity-related traits	2.000000e-06
GCST001762_702	Obesity-related traits	2.000000e-06
GCST006231_64	Mean arterial pressure	4.000000e-06
GCST010396_199	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004746	lipoprotein-associated phospholipase A(2) measurement
EFO:0005000	leptin measurement
EFO:0005106	body composition measurement
EFO:0006340	mean arterial pressure
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1926497 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 14,048 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL51085	EBSELEN	3	13,237
CHEMBL4303187	SETANAXIB	2	811

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — NADPH oxidases

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
NSC 780521	Inhibition	6.64	pIC50
setanaxib	Inhibition	6.39	pKi
compound 7c [PMID: 22041175]	Inhibition	6.38	pKi

ChEMBL bioactivities

29 potent at pChembl≥5 of 48 total, top 29 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	IC50	20	nM	DIPHENYLENEIODONIUM CHLORIDE
6.44	Ki	360	nM	CHEMBL1927146
6.39	Ki	410	nM	SETANAXIB
6.38	Ki	414	nM	CHEMBL1927147
6.32	Ki	475	nM	CHEMBL1927150
6.31	Ki	490	nM	CHEMBL1927160
6.26	Ki	543	nM	CHEMBL1927157
6.24	IC50	570	nM	CHEMBL5218591
6.24	IC50	570	nM	CHEMBL5398181
6.23	Ki	590	nM	CHEMBL1927145
6.23	Ki	585	nM	CHEMBL1927151
6.21	Ki	615	nM	CHEMBL1927149
6.21	Ki	610	nM	CHEMBL1927158
6.17	Ki	670	nM	CHEMBL1927148
6.16	EC50	700	nM	EBSELEN
6.16	Ki	690	nM	CHEMBL1927154
6.16	Ki	690	nM	CHEMBL1927159
6.14	Ki	730	nM	CHEMBL1927153
6.13	Ki	740	nM	CHEMBL1927152
6.02	Ki	955	nM	CHEMBL1927155
5.94	Ki	1150	nM	CHEMBL1927156
5.85	Ki	1425	nM	CHEMBL1926690
5.75	IC50	1800	nM	CHEMBL4210329
5.69	IC50	2060	nM	CHEMBL6173563
5.68	IC50	2100	nM	CHEMBL4210329
5.50	IC50	3130	nM	CELASTROL
5.33	IC50	4720	nM	CHEMBL6141807
5.28	IC50	5200	nM	CHEMBL6148605
5.19	IC50	6500	nM	CHEMBL6151297

PubChem BioAssay actives

48 with measured affinity, of 90 total; 24 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-iodoniatricyclo[7.4.0.02,7]trideca-1(13),2,4,6,9,11-hexaene chloride	2013276: Inhibition of human NOX5 expressed in HEK293 cells assessed as inhibition of ionomycin-induced hydrogen peroxide production pretreated for 15 mins followed by ionomycin stimulation and measured after 10 mins by Amplex Red based fluorescence analysis	ic50	0.0200	uM
4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.3600	uM
2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	2013294: Binding affinity to human NOX5 assessed as inhibition constant	ki	0.4100	uM
13-benzyl-4-(2-chlorophenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.4140	uM
4-(2-chlorophenyl)-13-[(3-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.4750	uM
4-(2-chlorophenyl)-12-oxa-4,5,9-triazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.4900	uM
4-(2-chlorophenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.5430	uM
2-N-(3,4-dimethylphenyl)-6-[[4-(4-methylphenyl)piperazin-1-yl]methyl]-1,3,5-triazine-2,4-diamine	2013311: Inhibition of NOX5 (unknown origin)	ic50	0.5700	uM
2-N-(3,4-dimethylphenyl)-6-[4-(4-methylphenyl)piperazin-1-yl]-1,3,5-triazine-2,4-diamine	1917073: Inhibition of human NOX5	ic50	0.5700	uM
4-(2-chlorophenyl)-13-[(4-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.5850	uM
tert-butyl 4-(2-chlorophenyl)-3,8-dioxo-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-13-carboxylate	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.5900	uM
4-(2-methoxyphenyl)-13-(pyridin-2-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6100	uM
4-(2-chlorophenyl)-13-[(2-chlorophenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6150	uM
13-benzyl-4-(2-methoxyphenyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6700	uM
4-(2-methoxyphenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6900	uM
4-(2-chlorophenyl)-13-[(4-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.6900	uM
2-phenyl-1,2-benzoselenazol-3-one	2013280: Inhibition of NOX5 (unknown origin) transfected in HEK cells	ec50	0.7000	uM
4-(2-chlorophenyl)-13-[(3-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.7300	uM
4-(2-chlorophenyl)-13-[(2-methoxyphenyl)methyl]-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.7400	uM
4-(2-chlorophenyl)-13-(furan-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	0.9550	uM
4-(2-chlorophenyl)-13-(pyridin-3-ylmethyl)-4,5,9,13-tetrazatricyclo[7.5.0.02,6]tetradeca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.1500	uM
12-benzyl-4-(2-chlorophenyl)-4,5,9,12-tetrazatricyclo[7.4.0.02,6]trideca-1,6-diene-3,8-dione;hydrochloride	635432: Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	ki	1.4250	uM
2-(3-benzyltriazolo[4,5-d]pyrimidin-7-yl)sulfanyl-1,3-benzoxazole	2013285: Inhibition of human NOX5 transfected in HEK cells assessed as PMA-induced hydrogen peroxide production pre-incubated for 10 mins and measured after 15 mins by Amplex-res based fluorescence assay	ic50	2.1000	uM
(2R,4aS,6aR,6aS,14aS,14bR)-10-hydroxy-2,4a,6a,6a,9,14a-hexamethyl-11-oxo-1,3,4,5,6,13,14,14b-octahydropicene-2-carboxylic acid	2013276: Inhibition of human NOX5 expressed in HEK293 cells assessed as inhibition of ionomycin-induced hydrogen peroxide production pretreated for 15 mins followed by ionomycin stimulation and measured after 10 mins by Amplex Red based fluorescence analysis	ic50	3.1300	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
methyl vanillate	increases expression	1
bisphenol A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
cyfluthrin	increases expression, decreases reaction	1
chromium hexavalent ion	increases expression	1
CGP 52608	affects binding, increases reaction	1
dalcetrapib	increases expression	1
torcetrapib	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
inotodiol	decreases reaction, increases expression	1
anacetrapib	decreases expression	1
Catechin	affects cotreatment, increases expression	1
Glucose	decreases expression	1
Hydrogen Peroxide	increases expression, decreases reaction	1
Isoflavones	affects expression	1
Melatonin	decreases reaction, increases expression	1
Methapyrilene	decreases methylation	1
Nitric Oxide	increases reaction, increases chemical synthesis	1
Nitrogen Dioxide	decreases expression	1
Oxygen	affects cotreatment, increases expression, decreases expression	1
Valproic Acid	increases methylation	1
Vanadates	decreases expression	1
Cadmium Chloride	increases expression	1
Dexmedetomidine	decreases expression, increases expression, affects reaction	1

ChEMBL screening assays

12 unique, capped per target: 11 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1931065	Functional	Antagonist activity at human NOX5 assessed as inhibition of ROS production after 20 mins by cell-free amplex red assay	Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives as novel dual Nox4/Nox1 inhibitors. — Bioorg Med Chem
CHEMBL3391330	Binding	Inhibition of full length human NOX5 transfected in HEK cells assessed as inhibition of ionomycin-stimulated ROS generation by chemiluminescence assay	Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors. — Medchemcomm

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1PB	Abcam K-562 NOX5 KO	Cancer cell line	Female
CVCL_D2KX	Abcam Raji NOX5 KO	Cancer cell line	Male
CVCL_D9LL	Ubigene HEK293 NOX5 KO	Transformed cell line	Female
CVCL_WQ14	Abcam Jurkat NOX5 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.