Peroxiredoxin 5 (PRDX5)

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Peroxiredoxin 5 (PRDX5)

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Peroxiredoxin 5 (PRDX5)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxiredoxin 5 (PRDX5)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">Thioredoxin</td>
<td>Electron donor, regeneration</td>
</tr>
<tr>
<td class="label">Sulfiredoxin</td>
<td>Overoxidation repair</td>
</tr>
<tr>
<td class="label">[SOD2](/proteins/sod2-protein)</td>
<td>Superoxide detoxification</td>
</tr>
<tr>
<td class="label">[GPX4](/proteins/gpx4-protein)</td>
<td>Lipid peroxidation</td>
</tr>
<tr>
<td class="label">p66Shc</td>
<td>Mitochondrial ROS</td>
</tr>
<tr>
<td class="label">ASK1</td>
<td>MAPK signaling</td>
</tr>
<tr>
<td class="label">DJ-1</td>
<td>Redox sensor</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/hepatitis" style="color:#ef9a9a">Hepatitis</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>

...

Peroxiredoxin 5 (PRDX5)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxiredoxin 5 (PRDX5)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">Thioredoxin</td>
<td>Electron donor, regeneration</td>
</tr>
<tr>
<td class="label">Sulfiredoxin</td>
<td>Overoxidation repair</td>
</tr>
<tr>
<td class="label">[SOD2](/proteins/sod2-protein)</td>
<td>Superoxide detoxification</td>
</tr>
<tr>
<td class="label">[GPX4](/proteins/gpx4-protein)</td>
<td>Lipid peroxidation</td>
</tr>
<tr>
<td class="label">p66Shc</td>
<td>Mitochondrial ROS</td>
</tr>
<tr>
<td class="label">ASK1</td>
<td>MAPK signaling</td>
</tr>
<tr>
<td class="label">DJ-1</td>
<td>Redox sensor</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a>, <a href="/wiki/hepatitis" style="color:#ef9a9a">Hepatitis</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>

<div style="float: right; margin: 0 0 1em 1em; padding: 1em; background: #f8f9fa; border: 1px solid #ddd; border-radius: 8px; font-size: 0.9em; max-width: 300px;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">PRDX5 Protein</h3>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px 8px;"><strong>Gene</strong></td><td>[PRDX5](/genes/prdx5)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>UniProt ID</strong></td><td>[P30044](https://www.uniprot.org/uniprot/P30044)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>PDB Structures</strong></td><td>[1HD2](https://www.rcsb.org/structure/1HD2), [1UR4](https://www.rcsb.org/structure/1UR4)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Molecular Weight</strong></td><td>22.0 kDa</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Amino Acids</strong></td><td>214</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Subcellular Location</strong></td><td>Cytosol, mitochondria, peroxisomes, nucleus</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Protein Family</strong></td><td>Peroxiredoxin family (Prx5 subfamily)</td></tr>
</table>
</div>

Overview

Peroxiredoxin 5 (PRDX5), also known as Alu co-repressor 1 (ACR1) or peroxisomal peroxiredoxin, is a unique atypical 2-Cys peroxiredoxin with broad substrate specificity and widespread subcellular distribution[@knoops1999]. Encoded by the [PRDX5](/genes/prdx5) gene on chromosome 11q13, PRDX5 is the most recently evolved peroxiredoxin and displays distinct structural and functional properties compared to other family members[@rhee2001].

PRDX5 is distinguished by its ability to reduce hydrogen peroxide, organic hydroperoxides, and peroxynitrite with high efficiency, making it a versatile component of the cellular antioxidant defense system[@dubuisson2004]. Its unique subcellular localization pattern—present in cytosol, mitochondria, peroxisomes, and nucleus—enables compartment-specific protection against oxidative stress, a feature particularly important in the metabolically active and oxidatively vulnerable brain[@seo2000].

Structure and Domain Architecture

PRDX5 has a unique structural arrangement among peroxiredoxins[@declercq2001]:

Core Structure

Thioredoxin fold: Characteristic α/β structure shared with other peroxiredoxins
Six α-helices and seven β-strands: Distinct from typical 2-Cys peroxiredoxins
Monomeric active form: Unlike dimeric typical 2-Cys peroxiredoxins

Catalytic Residues

Peroxidatic Cysteine (Cys-47)

Located in N-terminal region
Reacts with peroxide substrates
Forms sulfenic acid intermediate (Cys-SOH)

Resolving Cysteine (Cys-151)

Located in C-terminal region
Resolves sulfenic acid via disulfide bond formation
Characteristic of atypical 2-Cys mechanism

Subcellular Targeting Sequences

N-terminal mitochondrial targeting sequence (residues 1-20): Cleaved upon import
C-terminal peroxisomal targeting signal (SKL motif): PTS1 targeting
Alternative translation start sites: Generate cytosolic/nuclear isoforms

Active Site Architecture

Hydrophobic pocket: Accommodates diverse peroxide substrates
Arg-127 and Thr-44: Stabilize transition state
Trp-88: Modulates active site accessibility

Normal Function in the Nervous System

Antioxidant Defense

PRDX5 provides broad-spectrum peroxide detoxification[@wood2003]:

Hydrogen peroxide (H₂O₂): High catalytic efficiency (k ≈ 10⁷ M⁻¹s⁻¹)

Organic hydroperoxides: Lipid peroxides from membrane oxidation

Peroxynitrite (ONOO⁻): Reactive nitrogen species detoxification

Hypochlorous acid (HOCl): Inflammatory oxidant neutralization

Compartment-Specific Protection

The unique subcellular distribution of PRDX5 enables targeted protection[@banmeyer2005]:

Mitochondrial PRDX5: Protects respiratory chain from oxidative damage
Peroxisomal PRDX5: Detoxifies H₂O₂ generated by fatty acid oxidation
Cytosolic PRDX5: General oxidative stress response
Nuclear PRDX5: Protects DNA and transcription factors from oxidation

Redox Signaling Regulation

Beyond detoxification, PRDX5 modulates redox signaling[@kang2005]:

H₂O₂ signaling: Transiently modulates local H₂O₂ concentrations
Transcription factor regulation: Protects redox-sensitive TFs
MAPK signaling: Influences p38 and JNK activation

Role in Neurodegeneration

Alzheimer's Disease

PRDX5 alterations in AD include[@kattare2020]:

Expression Changes

Upregulation in AD brain: Compensatory response to oxidative stress
Increased in amyloid plaques: Associated with neuroinflammatory regions
Co-localization with [tau](/proteins/tau): Found in neurofibrillary tangle-bearing [neurons](/entities/neurons)

Neuroprotective Mechanisms

[Aβ](/proteins/amyloid-beta)-induced oxidative stress protection: Reduces Aβ toxicity
Mitochondrial protection: Preserves respiratory function
Anti-inflammatory effects: Limits microglial [ROS](/entities/reactive-oxygen-species) production

Parkinson's Disease

PRDX5 plays protective roles in PD[@de2013]:

Dopaminergic Neuron Protection

MPP+ resistance: Reduces MPTP model neurotoxicity
[α-synuclein](/proteins/alpha-synuclein) oxidation protection: Limits protein carbonylation
Mitochondrial complex I support: Protects electron transport

Nigrostriatal Vulnerability

High basal expression: In substantia nigra pars compacta
Dopamine oxidation buffering: Handles quinone and ROS byproducts
Iron-sulfur cluster protection: Preserves Fe-S enzyme function

Huntington's Disease

In HD models, PRDX5[@piantadosi2017]:

Reduces mutant [huntingtin](/proteins/huntingtin) aggregation
Protects against 3-nitropropionic acid toxicity
Preserves mitochondrial function

Amyotrophic Lateral Sclerosis

PRDX5 affects motor neuron survival via[@knoops2011]:

SOD1 mutant toxicity: Reduces oxidative damage
Glutamate excitotoxicity: Limits downstream ROS production
[TDP-43](/mechanisms/tdp-43-proteinopathy) oxidation: Prevents pathological aggregation

Multiple Sclerosis

PRDX5 is implicated in MS pathology through[@saini2018]:

Demyelination resistance: Protects oligodendrocytes
Inflammatory mediator reduction: Limits oxidative burst from [microglia](/cell-types/microglia-neuroinflammation)
Axonal preservation: Maintains mitochondrial transport

Therapeutic Targeting

Pharmacological Induction

Approaches to boost PRDX5 activity[@thimmulappa2002]:

Nrf2 activators: Sulforaphane, dimethyl fumarate upregulate PRDX5
Sirtuin activators: Resveratrol may enhance PRDX5 expression
Hormetic stress: Mild oxidative stress induces compensatory PRDX5

Direct Enhancement

Strategies for direct PRDX5 potentiation[@woo2005]:

Sulfiredoxin activation: Promotes PRDX5 regeneration
Small molecule stabilizers: Compounds that prevent overoxidation
Gene therapy: AAV-PRDX5 delivery to vulnerable neurons

Combination Approaches

Synergistic strategies include[@kim2014]:

Multi-peroxiredoxin induction: PRDX5 + PRDX3 + PRDX6
Glutathione pathway support: GSH + PRDX5 combination
Mitochondrial antioxidants: CoQ10 + PRDX5 synergy

Biomarker Potential

PRDX5 as a disease biomarker[@manuel2018]:

CSF levels: Elevated in neuroinflammatory conditions
Blood markers: Oxidized PRDX5 indicates systemic oxidative stress
Imaging: Potential PET tracer target for oxidative stress mapping

Protein-Protein Interactions

Summary

PRDX5 is a versatile atypical 2-Cys peroxiredoxin with unique subcellular distribution and broad substrate specificity. Its ability to detoxify hydrogen peroxide, organic hydroperoxides, and peroxynitrite makes it a critical component of the brain's antioxidant defense system. PRDX5 neuroprotection spans multiple neurodegenerative diseases, with particular importance in conditions involving mitochondrial dysfunction and oxidative stress.

External Links

[UniProt: P30044](https://www.uniprot.org/uniprot/P30044)
[NCBI Gene: 25824](https://www.ncbi.nlm.nih.gov/gene/25824)
[InterPro: IPR000866](https://www.ebi.ac.uk/interpro/entry/IPR000866/)

References

[Knoops B, Clippe A, Bogard C, et al, Cloning and characterization of AOEB166, a novel mammalian antioxidant enzyme of the peroxiredoxin family (1999)](https://doi.org/10.1074/jbc.274.43.30451)

[Rhee SG, Kang SW, Chang TS, et al, Peroxiredoxin, a novel family of peroxidases (2001)](https://doi.org/10.1080/15216540252774748)

[Dubuisson M, Vander Stricht D, Clippe A, et al, Human peroxiredoxin 5 is a peroxynitrite reductase (2004)](https://doi.org/10.1016/j.febslet.2004.06.080)

[Seo MS, Kang SW, Kim K, et al, Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate (2000)](https://doi.org/10.1074/jbc.M001890200)

[Declercq JP, Evrard C, Clippe A, et al, Crystal structure of human peroxiredoxin 5, a novel type of mammalian peroxiredoxin at 1.5 Å resolution (2001)](https://doi.org/10.1006/jmbi.2001.4853)

[Wood ZA, Poole LB, Karplus PA, Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling (2003)](https://doi.org/10.1126/science.1080405)

[Banmeyer I, Marchand C, Clippe A, Knoops B, Human mitochondrial peroxiredoxin 5 protects from mitochondrial DNA damages induced by hydrogen peroxide (2005)](https://doi.org/10.1016/j.freeradbiomed.2004.09.026)

[Kang SW, Rhee SG, Chang TS, et al, 2-Cys peroxiredoxin function in intracellular signal transduction (2005)](https://doi.org/10.1089/ars.2005.7.1257)

[Kattare MD, Owusu-Ansah E, Kwon J, et al, Peroxiredoxin 5 regulates oxidative stress in Alzheimer's disease (2020)](https://doi.org/10.3233/JAD-191255)

[De Simoni S, Linardopoulos V, Mistry R, et al, Peroxiredoxin 5 protects against oxidative stress in MPP+ model of Parkinson's disease (2013)](https://doi.org/10.1016/j.freeradbiomed.2013.07.033)

[Piantadosi A, Bakker A, Bastian AJ, et al, Peroxiredoxin 5 deficiency exacerbates 3-nitropropionic acid-induced neurotoxicity (2017)](https://doi.org/10.1016/j.brainres.2017.04.003)

[Knoops B, Goemaere J, Van der Eecken V, Govaerts C, Peroxiredoxin 5 in neurodegenerative diseases (2011)](https://doi.org/10.1016/j.freeradbiomed.2011.04.006)

[Saini H, Fernandez-Castaneda A, Jacquelin C, et al, Peroxiredoxin 5 is elevated in multiple sclerosis and protects oligodendrocytes from oxidative stress (2018)](https://doi.org/10.1177/1352458518774628)

[Thimmulappa RK, Mai KH, Srisuma S, et al, Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray (2002)](https://pubmed.ncbi.nlm.nih.gov/12234984/)

[Woo HA, Jeong W, Chang TS, et al, Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-Cys peroxiredoxins (2005)](https://doi.org/10.1074/jbc.C400496200)

[Kim JH, Lee JH, Kim SY, et al, Peroxiredoxin 5 attenuates ischemia/reperfusion-induced neuronal damage (2014)](https://doi.org/10.1016/j.neulet.2014.07.003)

[Manuel I, Barreda-Gómez G, González de San Román E, et al, Neuroprotective effects of peroxiredoxin 5 in neurodegenerative diseases (2018)](https://doi.org/10.1016/j.neuropharm.2018.03.031)

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Related Entities

PRDX5PROTEIN

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slug	proteins-prdx5-protein
kg_node_id	PRDX5PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-70103a2dcc21
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-prdx5-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Peroxiredoxin 5 (PRDX5)

Peroxiredoxin 5 (PRDX5)

Peroxiredoxin 5 (PRDX5)

Overview

Structure and Domain Architecture

Core Structure

Catalytic Residues

Peroxidatic Cysteine (Cys-47)

Resolving Cysteine (Cys-151)

Subcellular Targeting Sequences

Active Site Architecture

Normal Function in the Nervous System

Antioxidant Defense

Compartment-Specific Protection

Redox Signaling Regulation

Role in Neurodegeneration

Alzheimer's Disease

Expression Changes

Neuroprotective Mechanisms

Parkinson's Disease

Dopaminergic Neuron Protection

Nigrostriatal Vulnerability

Huntington's Disease

Amyotrophic Lateral Sclerosis

Multiple Sclerosis

Therapeutic Targeting

Pharmacological Induction

Direct Enhancement

Combination Approaches

Biomarker Potential

Protein-Protein Interactions

Summary

See Also

External Links

References

💬 Discussion