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 neutralizationCompartment-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.
See Also
- [PRDX5 Gene](/genes/prdx5)
- [Oxidative Stress](/mechanisms/oxidative-stress)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
- Peroxiredoxin Family
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
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)