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PRDX4

gene
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Also known as AOE37-2

Summary

PRDX4 (peroxiredoxin 4, HGNC:17169) is a protein-coding gene on chromosome Xp22.11, encoding Peroxiredoxin-4 (Q13162). Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.

The protein encoded by this gene is an antioxidant enzyme and belongs to the peroxiredoxin family. The protein is localized to the cytoplasm. Peroxidases of the peroxiredoxin family reduce hydrogen peroxide and alkyl hydroperoxides to water and alcohol with the use of reducing equivalents derived from thiol-containing donor molecules. This protein has been found to play a regulatory role in the activation of the transcription factor NF-kappaB.

Source: NCBI Gene 10549 — RefSeq curated summary.

At a glance

  • Clinical variants (ClinVar): 87 total
  • Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈8% of expected missense variation)
  • GTEx eGene: eQTL in 35 tissues, sQTL in 0 (q < 0.05)
  • ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
  • MANE Select transcript: NM_006406
  • Interaction hub: 2,358 STRING partners (top 5% of genes corpus-wide)
  • Notable: 87 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:17169
Approved symbolPRDX4
Nameperoxiredoxin 4
LocationXp22.11
Locus typegene with protein product
StatusApproved
AliasesAOE37-2
Ensembl geneENSG00000123131
Ensembl biotypeprotein_coding
OMIM300927
Entrez10549

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 14 nonsense_mediated_decay, 11 protein_coding, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000379341

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 3

ENST00000379341, ENST00000379331, ENST00000379349, ENST00000439422, ENST00000495599, ENST00000887283, ENST00000931168, ENST00000931169, ENST00000988484, ENST00000988485, ENST00000988486, ENST00000988487, ENST00000988489, ENST00001038760, ENST00001084463, ENST00001084470, ENST00001084471, ENST00001084474, ENST00001084476, ENST00001095693, ENST00001095694, ENST00001117752, ENST00001117753, ENST00001117754, ENST00001124129, ENST00001136491

RefSeq mRNA: 1 — MANE Select: NM_006406 NM_006406

CCDS: CCDS14206

Canonical transcript exons

ENST00000379341 — 7 exons

ExonStartEnd
ENSE000008362352368239623682526
ENSE000008362362368367123683705
ENSE000018282732368628523686397
ENSE000018580702366749323667811
ENSE000034959432367152923671646
ENSE000035128372367499023675106
ENSE000037891002367916523679287

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 155.0809 / max 1791.9174, expressed in 1820 samples.

Highest expression (Bgee): body of pancreas, pancreas, tibia, adrenal tissue, islet of Langerhans.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PRDX4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 35 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 35 significant tissue × QTL associations:

TissueQTLq-valueSlopeLead variant
Muscle Skeletaleqtl2.5e-31-0.34X:23620988:A:G
Esophagus Musculariseqtl1.1e-17+0.34X:23661817:A:T
Skin Sun Exposed Lower legeqtl4.2e-17+0.14X:23666905:C:T
Nerve Tibialeqtl7.1e-15+0.14X:23666905:C:T
Artery Tibialeqtl1.4e-14+0.12X:23689710:G:A
Esophagus Mucosaeqtl1.5e-14+0.14X:23679368:G:A
Thyroideqtl8.9e-12+0.14X:23681716:T:A
Brain Cerebellumeqtl2.1e-11+0.30X:23679368:G:A
Colon Sigmoideqtl4.0e-11+0.19X:23681101:G:T
Colon Transverseeqtl1.4e-09+0.12X:23671242:A:G
Brain Hippocampuseqtl5.2e-08+0.22X:23683293:A:C
Brain Cerebellar Hemisphereeqtl7.2e-08+0.19X:23666450:G:A
Esophagus Gastroesophageal Junctioneqtl6.7e-07+0.26X:23660381:C:CT
Adipose Subcutaneouseqtl1.9e-06+0.12X:23689710:G:A
Brain Frontal Cortex BA9eqtl4.8e-06+0.20X:23666450:G:A
Brain Spinal cord cervical c-1eqtl2.1e-05+0.19X:23679368:G:A
Cells Cultured fibroblastseqtl2.7e-05+0.07X:23676359:A:T
Brain Nucleus accumbens basal gangliaeqtl3.1e-05+0.17X:23668070:C:T
Brain Anterior cingulate cortex BA24eqtl5.4e-05+0.21X:23666450:G:A
Lungeqtl9.9e-05+0.06X:23668070:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter IDTPM avgSamples expressed
195764128.28591820
19576526.78441787
1957610.01064

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
body of pancreasUBERON:000115099.47gold quality
pancreasUBERON:000126498.99gold quality
tibiaUBERON:000097998.93gold quality
adrenal tissueUBERON:001830398.81gold quality
islet of LangerhansUBERON:000000698.62gold quality
parotid glandUBERON:000183198.52gold quality
stromal cell of endometriumCL:000225598.48gold quality
type B pancreatic cellCL:000016998.40gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099198.33gold quality
right testisUBERON:000453498.28gold quality
left testisUBERON:000453398.25gold quality
adult organismUBERON:000702398.20gold quality
cartilage tissueUBERON:000241898.17gold quality
liverUBERON:000210797.75gold quality
deciduaUBERON:000245097.74gold quality
periodontal ligamentUBERON:000826697.68gold quality
testisUBERON:000047397.67gold quality
placentaUBERON:000198797.53gold quality
right lobe of liverUBERON:000111497.50gold quality
corpus epididymisUBERON:000435997.49gold quality
seminal vesicleUBERON:000099897.40gold quality
saliva-secreting glandUBERON:000104497.19gold quality
pituitary glandUBERON:000000797.17gold quality
ventricular zoneUBERON:000305397.11gold quality
right atrium auricular regionUBERON:000663197.03gold quality
endometriumUBERON:000129597.02gold quality
ascending aortaUBERON:000149697.02gold quality
thoracic aortaUBERON:000151597.00gold quality
minor salivary glandUBERON:000183096.97gold quality
adenohypophysisUBERON:000219696.96gold quality
cardiac atriumUBERON:000208196.94gold quality
right ovaryUBERON:000211896.83gold quality
left coronary arteryUBERON:000162696.81gold quality
gall bladderUBERON:000211096.80gold quality
descending thoracic aortaUBERON:000234596.79gold quality
tracheaUBERON:000312696.78gold quality
smooth muscle tissueUBERON:000113596.77gold quality
skin of hipUBERON:000155496.76gold quality
right coronary arteryUBERON:000162596.76gold quality
right adrenal glandUBERON:000123396.75gold quality
rectumUBERON:000105296.73gold quality
mucosa of sigmoid colonUBERON:000499396.70gold quality
nasal cavity mucosaUBERON:000182696.69gold quality
oral cavityUBERON:000016796.68gold quality
coronary arteryUBERON:000162196.64gold quality
peritoneumUBERON:000235896.64gold quality
omental fat padUBERON:001041496.64gold quality
adipose tissue of abdominal regionUBERON:000780896.63gold quality
left adrenal glandUBERON:000123496.62gold quality
olfactory segment of nasal mucosaUBERON:000538696.60gold quality
endocervixUBERON:000045896.57gold quality
body of stomachUBERON:000116196.57gold quality
left ovaryUBERON:000211996.57gold quality
mouth mucosaUBERON:000372996.57gold quality
male germ cellCL:000001596.53gold quality
ovaryUBERON:000099296.52gold quality
spermCL:000001996.47gold quality
right adrenal gland cortexUBERON:003582796.47gold quality
left adrenal gland cortexUBERON:003582596.38gold quality
calcaneal tendonUBERON:000370196.30gold quality
adrenal glandUBERON:000236996.28gold quality
pigmented layer of retinaUBERON:000178296.26gold quality
heart right ventricleUBERON:000208096.24gold quality
superficial temporal arteryUBERON:000161496.22gold quality
uterusUBERON:000099596.15gold quality
adrenal cortexUBERON:000123596.08gold quality
ectocervixUBERON:001224996.06gold quality
layer of synovial tissueUBERON:000761696.04gold quality
synovial jointUBERON:000221796.00gold quality
caput epididymisUBERON:000435895.94gold quality
pericardiumUBERON:000240795.92gold quality
aortaUBERON:000094795.90gold quality
adipose tissueUBERON:000101395.89gold quality
cardiac muscle of right atriumUBERON:000337995.89gold quality
left uterine tubeUBERON:000130395.88gold quality
stomachUBERON:000094595.86gold quality
parietal pleuraUBERON:000240095.86gold quality
connective tissueUBERON:000238495.82gold quality
body of uterusUBERON:000985395.78gold quality
female reproductive systemUBERON:000047495.77gold quality
pylorusUBERON:000116695.76gold quality
germinal epithelium of ovaryUBERON:000130495.75gold quality
epithelium of nasopharynxUBERON:000195195.72gold quality
myocardiumUBERON:000234995.71gold quality
thoracic mammary glandUBERON:000520095.69gold quality
right uterine tubeUBERON:000130295.68gold quality
myometriumUBERON:000129695.64gold quality
mammary glandUBERON:000191195.63gold quality
embryoUBERON:000092295.62gold quality
bronchial epithelial cellCL:000232895.53gold quality
epithelial cell of pancreasCL:000008395.50gold quality
mucosa of transverse colonUBERON:000499195.49gold quality
tibial nerveUBERON:000132395.46gold quality
colonic mucosaUBERON:000031795.44gold quality
cardia of stomachUBERON:000116295.44gold quality
heartUBERON:000094895.38gold quality
cervix squamous epitheliumUBERON:000692295.38gold quality
fundus of stomachUBERON:000116095.27gold quality
subcutaneous adipose tissueUBERON:000219095.25gold quality
tibial arteryUBERON:000761095.13gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 14.

ExperimentMarker?Max mean expression
E-HCAD-32yes1048.25
E-CURD-88yes131.52
E-HCAD-4yes69.01
E-HCAD-1yes64.28
E-MTAB-9467yes63.56
E-CURD-46yes61.46
E-CURD-122yes57.48
E-MTAB-8410yes42.04
E-HCAD-11yes26.28
E-HCAD-6yes18.08
E-CURD-112yes16.09
E-MTAB-10553yes15.64
E-MTAB-10042yes13.49
E-HCAD-31no21.20
E-ANND-3no0.00

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cellAxisnTPMProtein (IHC)
Pancreastissue1142.7high
Livertissue258.9medium
Ovarytissue111.0medium
Pituitary glandtissue95.6
Placentatissue90.3medium
Testistissue89.5high
Salivary glandtissue86.9low
Cervixtissue77.3medium
Stomach 1tissue76.9medium
Rectumtissue73.9low
Breasttissue70.0medium
Colontissue68.1medium
Parathyroid glandtissue65.0low
Urinary bladdertissue64.5medium
Tonsiltissue62.9low
Heart muscletissue62.7low
Fallopian tubetissue62.1medium
Adipose tissuetissue60.8medium
Gallbladdertissue60.6medium
Duodenumtissue60.2medium
Seminal vesicletissue59.6medium
Smooth muscletissue58.7low
Vaginatissue57.2low
Prostatetissue56.2low
Lymph nodetissue55.0medium
Adrenal glandtissue52.7medium
Appendixtissue50.8medium
Endometrium 1tissue49.6medium
Small intestinetissue48.3medium
Esophagustissue46.2low
Choroid plexustissue45.4
Thyroid glandtissue43.0medium
Frontal cortextissue38.9
Kidneytissue37.5low
Caudate putamentissue36.7
Lungtissue34.3medium
Skeletal muscletissue32.6medium
Bone marrowtissue32.3low
Spleentissue31.2low
Skin 1tissue28.5medium
Retinatissue27.9
Thymustissue24.7
Tonguetissue23.6
Epididymistissue18.4medium
Locus coeruleustissue16.5
Nucleus accumbenstissue15.7
Hippocampustissue11.7low
Cerebellumtissue10.8low
Cerebral cortextissue9.9medium
Somatosensory cortextissue9.9
Retrosplenial and cingulate cortextissue9.8
Hippocampal formationtissue9.7
Entorhinal cortextissue9.7
Temporal cortextissue9.7
Prefrontal cortextissue9.6
Occipital cortextissue9.5
Insular cortextissue9.3
Retrosplenial cortextissue9.0
Corpus callosumtissue8.9
Motor cortextissue8.8

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (97.4), Dorsal funiculus (white matter) (37.4), Lateral funiculus (white matter) (35.1), Anterior funiculus (white matter) (26.5), Nucleus raphe pallidus (25.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, NRF1

Functional genomics

Regional missense constraint (gnomAD)

ENST00000379341 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈8% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)Missense obs / expo/eConstrained
X:23,667,571–23,675,057105 / 114.20.92no
X:23,675,058–23,679,1822 / 16.50.12yes (p 3.5e-04)
X:23,679,183–23,686,33273 / 76.50.95no

Literature-anchored findings (GeneRIF, showing 40)

  • 2-Cys Prxs act in a mutually nonredundant and sometimes stress-specific fashion to protect human cells from oxidant injury. The substantial resistance of human cells to hydroperoxides may result in part from the additive action of multiple Prxs (PMID:12080185)
  • PRDX4 interacts with and regulates TBXA2R. (PMID:17644091)
  • Peroxiredoxin IV forms complex structures within the ER, consistent with the formation of homodecamers (PMID:18052930)
  • These results suggested that Prx IV involved in the 16alpha-OHE1-induced proliferation of MCF-7 cells has a proliferative effect and may be related to cancer development or progression. (PMID:18272409)
  • data suggested that TRAIL suppressed the PRDX4 gene at the transcriptional level and that downregulation of PRDX4 might facilitate cell death induced by TRAIL (PMID:19364504)
  • PRDX4 has a pivotal protective function against diabetes progression in this type 1 diabetes mellitus model (PMID:20446767)
  • These results suggest that Prdx-1 and Prdx-4 are essential for preventing respiratory syncytial virus-induced oxidative damage in a subset of nuclear intermediate filament and actin binding proteins in epithelial cells. (PMID:20610706)
  • PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. (PMID:21031435)
  • Here, the authors demonstrate that several members of the protein disulphide isomerase family are able to directly reduce this PrxIV disulphide and in the process become oxidized. (PMID:21057456)
  • Elevated serum levels of the antioxidant Prx4 were associated with an increased disease severity and adverse outcome of critically ill patients with sepsis. (PMID:21283059)
  • strong reduction in PRDX4 expression levels in APL correlates with increased trimethylation of histone 3 lysine residue 27 and 4 at the transcriptional start site of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. (PMID:21283726)
  • Srx-Prx IV axis is critical for lung cancer maintenance and metastasis, suggesting that targeting the Srx-Prx IV axis may provide unique effective strategies for cancer prevention and treatment. (PMID:21487000)
  • Data show that Keap1 and PRDX IV were overexpressed in the TNBC cohort. (PMID:21693047)
  • A proteomic approach for identification and localization of the pericellular components of chondrocytes (PMID:21698479)
  • Overexpression of PRDX4 and P4HA2 was significantly associated with lymphatic metastasis in oral cavity squamous cell carcinoma (PMID:21859152)
  • This study solved crystal structures of human Prx4 in three different redox forms and characterized the reaction features of Prx4 with hydrogen peroxide. (PMID:21916849)
  • Crystal structure of reduced and of oxidized peroxiredoxin IV enzyme reveals a stable oxidized decamer and a non-disulfide-bonded intermediate in the catalytic cycle (PMID:21994946)
  • Prdx4 inhibits G-CSF-induced signalling and proliferation in myeloid progenitors. (PMID:22045733)
  • A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
  • Reverse phase protein arrays verified that the overexpression of both PRDX3 and PRDX4 in prostate tumor samples is negatively correlated with the presence of the TMPRSS2-ERG gene fusion. (PMID:22424448)
  • data suggest that PRDX4 can be a novel target for glioblastoma multiforme therapies in the future (PMID:22916164)
  • these results indicate that two placental proteins, Prx3 and Prx4, may act as new placental immune targets. Production of antibodies against peroxiredoxins 3 and 4 may introduce a new autoimmune hypothesis in recurrent pregnancy loss. (PMID:23190175)
  • Elevated serum Prx4 levels are associated with a significantly higher risk of incident cardiovascular disease (CVD) events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. (PMID:23316297)
  • expression of Prxs I and IV, both at mRNA and protein levels, was associated with light chain secretion quantified by ELISA. (PMID:23737084)
  • Remarkably, the Prx4-dependent formation of native disulfide bonds was accelerated when PDI was combined with ERp46 or P5, suggesting that PDIs work synergistically to increase the rate and fidelity of oxidative protein folding. (PMID:23949117)
  • Data indicate that protein disulfide isomerase (PDI) and ERp44 dynamically localize Ero1alpha and peroxiredoxin 4 in early secretory compartment (ESC). (PMID:23979138)
  • expression of PRDX4 in PCOS ovaries appeared to be mediated through oxidative stress in GCs. We reported that the deficiency of antioxidant PRDX4 was associated with pathophysiological mechanism of PCOS. (PMID:24098506)
  • peroxiredoxin IV recycling in the endoplasmic reticulum is much less efficient than in the cytosol or mitochondria, leading to the protection of peroxiredoxin IV from hyperoxidation. (PMID:24403061)
  • The structure and function of PRDX4 as well as its sensitivity to hyperoxidation. [Review] (PMID:24450625)
  • Prx4 is a circulating antioxidant and is independently associated with increased risk of cardiovascular and all-cause mortality in T2DM. (PMID:24586984)
  • there is a significant difference in concentration of Prx4 between cardiac arrest patients with good and poor outcome (PMID:24617620)
  • Findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes (PMID:24893865)
  • these data suggest an important role of Prdx4 in maintaining insulin levels and improving the ER folding capacity also under conditions of a high insulin requirement. (PMID:25122762)
  • An off-pathway reaction in the Prx4-mediated oxidative protein folding. (PMID:25137134)
  • Positive Prx 4 expression is significantly correlated with recurrence and shorter disease-free survival in patients with early-stage lung squamous cell carcinoma. (PMID:26261544)
  • Prdx4 expression was closely related to follicular development and has aprominent role in protecting human and mouse granulosa cells from reactive oxygen species damage. (PMID:26917265)
  • levels of peroxiredoxin 4 are higher in patients with prediabetes, but are similar in subjects with and without insulin resistance, which suggests that the main factor for its increased levels is hyperglycaemia and not insulin sensitivity state. (PMID:27303935)
  • Results show that ERp44 binds the oxidized but not the reduced form of Prx4; the ERp44-Prx4 complex is formed via thiol-disulfide interchange reactions, and its crystal structure reveals a redox-dependent recognition. (PMID:27642162)
  • Significant reduction in mRNA and protein levels of PrdxIV was observed in HEK293 cells overexpressing pathologically relevant recombinant mutant GNE protein (D207V and V603L) compared with vector control. Downregulation of PrdxIV keep the ER in a reduced (redox) state that may contribute to misfolding and aggregation of proteins in GNE myopathy. (PMID:28895049)
  • Hepatocellular carcinoma (HCC) tumors with low expression of PRDX4 had higher ROS levels, malignancy, and associated with reduced overall survival. In HCC cell lines, its knockdown led to increased intracellular ROS level and suppressed cell proliferation, inducing cell death. These results indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression. (PMID:29687726)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_rerioprdx4ENSDARG00000069013
mus_musculusPrdx4ENSMUSG00000025289
rattus_norvegicusPrdx4ENSRNOG00000003763
drosophila_melanogasterPrx4FBGN0040308
caenorhabditis_elegansWBGENE00011110

Paralogs (4): PRDX1 (ENSG00000117450), PRDX6 (ENSG00000117592), PRDX3 (ENSG00000165672), PRDX2 (ENSG00000167815)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1859815) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)Records
oligozoospermia1
testicular atrophy1
oxidative stress1
decreased testis weight1
increased male germ cell apoptosis1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

OrganismUniProtIdentityMethod
Staphylococcus aureus subsp. aureus Mu50P0A0B5100.0%Diamond
Staphylococcus aureus subsp. aureus MW2P0A0B6100.0%Diamond
Staphylococcus aureus subsp. aureus NCTC 8325P0A0B7100.0%Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2P0A251100.0%Diamond
Salmonella enterica subsp. enterica serovar TyphiP0A252100.0%Diamond
Escherichia coli K-12P0AE08100.0%Diamond
Escherichia coli CFT073P0AE09100.0%Diamond
Escherichia coli O157:H7P0AE10100.0%Diamond
Shigella flexneriP0AE11100.0%Diamond
Candida albicans SC5314P0CU34100.0%Diamond
Mycobacterium tuberculosis variant bovis AF2122/97P65689100.0%Diamond
Staphylococcus aureus subsp. aureus N315P99074100.0%Diamond
Mycobacterium tuberculosis CDC1551P9WIE0100.0%Diamond
Mycobacterium tuberculosis H37RvP9WIE1100.0%Diamond
Staphylococcus aureus subsp. aureus USA300Q2FJN4100.0%Diamond
Macaca fascicularisQ2PFZ3100.0%Diamond
Staphylococcus aureus RF122Q2YVK2100.0%Diamond
Staphylococcus aureus subsp. aureus COLQ5HIR5100.0%Diamond
Staphylococcus aureus subsp. aureus MSSA476Q6GC91100.0%Diamond
Staphylococcus aureus subsp. aureus MRSA252Q6GJR7100.0%Diamond
Triticum aestivumP8060299.5%Diamond
Staphylococcus epidermidis RP62AQ5HRY199.5%Diamond
Staphylococcus epidermidis ATCC 12228Q8CMQ299.5%Diamond
Hordeum vulgareQ9646899.5%Diamond
Pongo abeliiQ5RC6399.4%Diamond
Myotis lucifugusQ6B4U999.0%Diamond
Spinacia oleraceaO2436498.5%Diamond
Helicobacter pylori 26695P2176298.5%Diamond
Helicobacter pylori J99P5687698.5%Diamond
Arabidopsis thalianaQ9629198.5%Diamond
Methanococcus maripaludis C5A4FWZ997.2%Diamond
Thermotoga petrophila RKU-1A5IIX797.2%Diamond
Methanococcus maripaludis S2Q6LY1997.2%Diamond
Thermotoga maritima MSB8Q9WZR497.2%Diamond
Bos taurusQ5E94797.0%Diamond
Cricetulus griseusQ8K3U796.5%Diamond
Methanothermobacter thermautotrophicus str. Delta HO2626295.7%Diamond
Methanothermobacter marburgensis str. MarburgQ5710995.7%Diamond
Pyrococcus abyssi GE5Q9UZV494.4%Diamond
Pyrococcus horikoshii OT3O5896694.0%Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

SymbolTypeEntrez
PTCHD1-ASncRNA100873065
PTCHD1protein-coding139411
ACOT9protein-coding23597
SAT1protein-coding6303
APOOprotein-coding79135
SAT1-DTncRNA105373148
CXorf58protein-coding254158

Protein

Protein identifiers

Peroxiredoxin-4 — Q13162 (reviewed: Q13162)

Alternative names: Antioxidant enzyme AOE372, Peroxiredoxin IV, Thioredoxin peroxidase AO372, Thioredoxin-dependent peroxide reductase A0372, Thioredoxin-dependent peroxiredoxin 4

All UniProt accessions (5): A6NG45, A6NJJ0, H7C3T4, Q13162, V9HW63

UniProt curated annotations — full annotation on UniProt →

Function. Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Regulates the activation of NF-kappa-B in the cytosol by a modulation of I-kappa-B-alpha phosphorylation.

Subunit / interactions. Homodimer; disulfide-linked, upon oxidation. 5 homodimers assemble to form a ring-like decamer. Can form heterodimers with PRDX1.

Subcellular location. Cytoplasm. Endoplasmic reticulum.

Post-translational modifications. The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) and sulphonic acid (C(P)-SO3H) instead of its condensation to a disulfide bond.

Miscellaneous. The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide. The disulfide is subsequently reduced by thioredoxin.

Similarity. Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.

RefSeq proteins (1): NP_006397* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000866AhpC/TSADomain
IPR013766Thioredoxin_domainDomain
IPR019479Peroxiredoxin_CDomain
IPR036249Thioredoxin-like_sfHomologous_superfamily
IPR050217PeroxiredoxinFamily

Pfam: PF00578, PF10417

Enzyme classification (BRENDA)

  • EC 1.11.1.24 — thioredoxin-dependent peroxiredoxin (BRENDA: 72 organisms, 110 substrates, 31 inhibitors, 72 Km, 50 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

SubstrateKm (mM)Measurements
H2O20.0004–11.723
CUMENE HYDROPEROXIDE0.0066–0.1918
THIOREDOXIN0.001–0.07947
TERT-BUTYL HYDROPEROXIDE—5
THIOREDOXIN A0.0009–0.01225
THIOREDOXIN B0.0022–0.02085
T-BUTYL HYDROPEROXIDE0.072–0.1934
THIOREDOXIN Q0.0007–0.00284
REDUCED THIOREDOXIN0.0024–0.0042
REDUCED THIOREDOXIN A0.0079–0.00872
ETHYL HYDROPEROXIDE0.00451
LINOLEIC ACID HYDROPEROXIDE0.1171
TRYPAREDOXIN 20.03191

Catalyzed reactions (Rhea)

  • a hydroperoxide + [thioredoxin]-dithiol = an alcohol + [thioredoxin]-disulfide + H2O (RHEA:62620)

UniProt features (33 total): strand 12, helix 9, turn 4, disulfide bond 2, sequence conflict 2, signal peptide 1, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDBTitleMethodResolution (Å)
2PN8Crystal structure of human peroxiredoxin 4 (thioredoxin peroxidase)X-RAY DIFFRACTION1.8
3TJJCrystal structure of human peroxiredoxin IV C245A mutant in sulfenylated formX-RAY DIFFRACTION1.91
3TJFCrystal Structure of human peroxiredoxin IV C51A mutant in reduced formX-RAY DIFFRACTION2.04
3TJKCrystal Structure of human peroxiredoxin IV C245A mutant in reduced formX-RAY DIFFRACTION2.09
3TKRCrystal structure of full-length human peroxiredoxin 4 with T118E mutationX-RAY DIFFRACTION2.1
3TKQCrystal structure of full-length human peroxiredoxin 4 with mixed conformationX-RAY DIFFRACTION2.22
3TJGCrystal Structure of human peroxiredoxin IV C51A mutant in oxidized formX-RAY DIFFRACTION2.24
4RQXCrystal structure of human peroxiredoxin 4(THIOREDOXIN PEROXIDASE) with MESNAX-RAY DIFFRACTION2.26
3TJBCrystal structure of wild-type human peroxiredoxin IVX-RAY DIFFRACTION2.38
3TKSCrystal structure of full-length human peroxiredoxin 4 in three different redox statesX-RAY DIFFRACTION2.4
3TKPCrystal structure of full-length human peroxiredoxin 4 in the reduced formX-RAY DIFFRACTION2.49
5HQPCrystal structure of the ERp44-peroxiredoxin 4 complexX-RAY DIFFRACTION2.6
8EKWCryo-EM structure of human PRDX4ELECTRON MICROSCOPY2.83
8EKYCryo-EM structure of the human PRDX4-ErP46 complexELECTRON MICROSCOPY3.47

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q13162-F184.590.72

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum; cytosol

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

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

Catalytic / active sites (1)

PositionRole
124cysteine sulfenic acid (-soh) intermediate

Disulfide bonds (2)

TypePositions
Interchain (with c-245)124
Interchain (with c-124)245

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

IDPathwayEvidence
R-HSA-6798695Neutrophil degranulationcurated
R-HSA-168256Immune System—
R-HSA-168249Innate Immune System—

MSigDB gene sets: 302 (showing top): MODULE_93, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GRUETZMANN_PANCREATIC_CANCER_DN, BASSO_B_LYMPHOCYTE_NETWORK, GOCC_SECRETORY_GRANULE, MODULE_151, GOBP_HYDROGEN_PEROXIDE_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, KYNG_DNA_DAMAGE_DN, GOBP_MALE_GAMETE_GENERATION, CEBPB_01

GO Biological Process (5): response to oxidative stress (GO:0006979), I-kappaB phosphorylation (GO:0007252), hydrogen peroxide catabolic process (GO:0042744), cell redox homeostasis (GO:0045454), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (10): thioredoxin peroxidase activity (GO:0008379), identical protein binding (GO:0042802), molecular adaptor activity (GO:0060090), molecular sequestering activity (GO:0140313), peroxidase activity (GO:0004601), protein binding (GO:0005515), antioxidant activity (GO:0016209), oxidoreductase activity (GO:0016491), peroxiredoxin activity (GO:0051920), thioredoxin-dependent peroxiredoxin activity (GO:0140824)

GO Cellular Component (8): extracellular region (GO:0005576), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813), cytoplasm (GO:0005737)

Reactome top-level categories

2 top-level categories:

CategoryPathways
Innate Immune System1
Immune System1

GO top-level categories

27 GO namespaces:

CategoryTerms
molecular_function3
cellular anatomical structure3
binding2
intracellular membrane-bounded organelle2
cytoplasm2
response to stress1
protein phosphorylation1
canonical NF-kappaB signal transduction1
catabolic process1
hydrogen peroxide metabolic process1
cellular homeostasis1
cellular detoxification1
thioredoxin-dependent peroxiredoxin activity1
protein binding1
antioxidant activity1
oxidoreductase activity, acting on peroxide as acceptor1
cellular oxidant detoxification1
catalytic activity1
peroxidase activity1
peroxiredoxin activity1
endomembrane system1
secretory granule1
cytoplasmic vesicle lumen1
extracellular vesicle1
intracellular organelle lumen1
ficolin-1-rich granule1
intracellular anatomical structure1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO termNSEvidence
cytosolCCdirect assay
endoplasmic reticulumCCdirect assay
extracellular exosomeCChigh-throughput assay
nucleusCChigh-throughput assay
molecular adaptor activityMFexperiment
molecular sequestering activityMFdirect assay

Protein interactions and networks

STRING

showing 15 of 2,358 interactions by confidence (×1000):

Protein AProtein BPartner UniProtScore
PRDX4GLULP15104782
PRDX4PRDX5P30044753
PRDX4TXNP10599696
PRDX4SRXN1Q9BYN0639
PRDX4GPX7Q96SL4638
PRDX4GPX8Q8TED1630
PRDX4ERO1AQ96HE7618
PRDX4TXNDC5Q8NBS9574
PRDX4TXNRD1Q16881563
PRDX4GPX4P36969553
PRDX4ERO1BQ86YB8550
PRDX4GLRXP35754550
PRDX4ERP44Q9BS26539
PRDX4TXN2Q99757537
PRDX4P4HBP07237531

IntAct

Human interaction partners of PRDX4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

28 partners by confidence:

PartnerInteraction typeMIscoreRecords
ATXN1physical association0.6703
LBPphysical association0.6004
TBXA2Rphysical association0.5903
PRDX1physical association0.5702
NR4A1physical association0.5502
PDIA6oxidoreductase activity electron transfer reaction0.5202
P4HBoxidoreductase activity electron transfer reaction0.4402
PDIA3oxidoreductase activity electron transfer reaction0.4402
TXNDC5oxidoreductase activity electron transfer reaction0.4402
A1BGphysical association0.3701
ALG12physical association0.3701
APOBphysical association0.3701
CFHR1physical association0.3701
CFHR3physical association0.3701
CLIC1physical association0.3701
CYP27A1physical association0.3701
DUSP23physical association0.3701
EP300physical association0.3701
HDAC6physical association0.3701
MAP4K2physical association0.3701
MT-CO1physical association0.3701
PLGphysical association0.3701
PRDX2physical association0.3701
PRDX3physical association0.3701
RCHY1physical association0.3701
SULT2A1physical association0.3701
TTF2physical association0.3701
VTNphysical association0.3701

BioGRID (314 interactions; top human partners by supporting records): PRDX1 (Two-hybrid; 11 records), AGR2 (Proximity Label-MS; 4 records), OTUD1 (Proximity Label-MS; 4 records), CUL3 (Affinity Capture-MS; 3 records), INS (Affinity Capture-MS; 3 records), TBXA2R (Two-hybrid; 3 records), AURKA (Affinity Capture-MS; 2 records), CCNF (Affinity Capture-MS; 2 records), CLIC1 (Affinity Capture-MS; 2 records), CTSB (Affinity Capture-MS; 2 records), CTSS (Affinity Capture-MS; 2 records), DPP4 (Affinity Capture-MS; 2 records), HDAC6 (Affinity Capture-MS; 2 records), HSPA5 (Affinity Capture-Western; 2 records), HUWE1 (Affinity Capture-MS; 2 records)

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO termPartnersFoldFDR
protein folding518.5×2e-03

Disease & clinical

Genetic variants

Variant evidence for PRDX4: 87 ClinVar records (0 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation.

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance24
Likely benign0
Benign1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 440):

Position(s)EffectΔscoreSites
X:23671647–23671648donor_loss1.00005
X:23674988–23674989acceptor_loss1.00006
X:23675107–23675108donor_loss1.00005
X:23682386acceptor_gain1.0000
X:23682393acceptor_gain1.0000
X:23682394–23682395acceptor_loss1.00005
X:23682524donor_gain1.0000
X:23682527–23682528donor_loss1.00004
X:23683659acceptor_gain1.0000
X:23683706–23683707donor_loss1.00004

AlphaMissense

895 missense substitutions predicted likely pathogenic (of 1,730 scored), across 186 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

ResidueLikely-pathogenic substitutionsMean am_pathogenicityMax am_pathogenicity
D15180.9970.999
D17980.9960.999
H15680.9940.999
D21880.9930.998
D11980.9880.997
F12280.9881.000
F12080.9861.000
F11580.9760.998
F13880.9760.999
F26780.9760.995
F13180.9630.997
F20380.9580.998
N21780.9510.999
F23580.9420.996
D20680.9400.997
F9880.9200.996
H19780.8650.985
D23980.8600.971
D22680.8180.963
F11380.8110.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

CancerPrognosticp-value
Kidney Renal Papillary Cell Carcinoma (TCGA)unfavorable2.37e-07
Kidney Renal Clear Cell Carcinoma (TCGA)favorable7.58e-06
Bladder Urothelial Carcinoma (TCGA)unfavorable9e-05
Kidney Chromophobe (TCGA)unfavorable0.000291
Liver Hepatocellular Carcinoma (TCGA)unfavorable0.000553
Breast Invasive Carcinoma (TCGA)unfavorable0.000809

Disease associations

OMIM: gene MIM:300927 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295812 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,601 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

MoleculeNamePhasePatents
CHEMBL1232461MOLIBRESIB21,601

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

VariantAssociationLevelDrugsPhenotypes
rs518329Dosage3docetaxelNon-Small Cell Lung Carcinoma

PharmGKB variants

1 variants:

VariantGenesLevelScore#Clin annotsDrugs
rs518329PRDX430.251docetaxel

Binding affinities (BindingDB)

2 measured of 2 human assays (4 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValue
CHEMBL5565154IC50350 nM
CHEMBL5653589KD1440 nM

ChEMBL bioactivities

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

pChemblTypeValueUnitMolecule
7.52Kd30.49nMCHEMBL5653589
7.52ED5030.49nMCHEMBL5653589
5.56Kd2733nMCHEMBL3752910
5.56ED502733nMCHEMBL3752910
5.00IC501e+04nMMOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 17 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149064: Binding affinity to human PRDX4 incubated for 45 mins by Kinobead based pull down assaykd0.0305uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149064: Binding affinity to human PRDX4 incubated for 45 mins by Kinobead based pull down assaykd2.7330uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide2178893: Inhibition of PRDX4 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysisic5010.0000uM

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
sodium arsenitedecreases expression, increases abundance, increases expression5
bisphenol Aaffects expression, decreases expression, increases expression3
Tobacco Smoke Pollutionaffects expression, increases expression3
Aerosolsdecreases expression, increases expression2
Benzo(a)pyreneaffects methylation, increases expression, increases methylation2
Cadmiumdecreases expression, increases abundance, increases expression2
Doxorubicinaffects expression, increases expression2
Hydrogen Peroxideaffects cotreatment, increases expression2
Valproic Acidaffects expression, increases expression2
Cyclosporinedecreases expression, increases expression2
Cadmium Chloridedecreases expression, increases abundance, increases expression2
moringinaffects cotreatment, decreases expression1
methylmercuric chlorideincreases expression1
beta-lapachonedecreases expression1
arseniteaffects binding, increases reaction1
tris(1,3-dichloro-2-propyl)phosphatedecreases expression1
16-hydroxyestroneincreases expression1
gallium nitratedecreases expression1
gossypol acetic acidincreases expression1
2,3-bis(3’-hydroxybenzyl)butyrolactoneincreases expression, affects cotreatment1
dibenzo(a,l)pyrenedecreases expression1
cyfluthrindecreases expression1
di-n-butylphosphoric acidaffects expression1
CD 437increases expression1
bisphenol Bincreases expression1
abrineincreases expression1
chromium histidinateincreases expression1
(+)-JQ1 compounddecreases expression1
Sunitinibincreases expression1
Arsenic Trioxideincreases expression1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4118781BindingBinding affinity to PRDX4 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assayStudies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

CellosaurusNameCategorySex
CVCL_B3ETAbcam HEK293T PRDX4 KOTransformed cell lineFemale
CVCL_E2HKHAP1 PRDX4 (-) 1Cancer cell lineMale
CVCL_E2HLHAP1 PRDX4 (-) 2Cancer cell lineMale
CVCL_E2HMHAP1 PRDX4 (-) 3Cancer cell lineMale
CVCL_E2HNHAP1 PRDX4 (-) 4Cancer cell lineMale
CVCL_E2HPHAP1 PRDX4 (-) 5Cancer cell lineMale

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PRDX4 across ~30M SureChEMBL compounds — explore on Sugi Predict.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.