Peroxiredoxin

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Family of antioxidant enzymes

title: "Peroxiredoxin" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["ec-1.11.1", "antioxidants", "gene-families"] description: "Family of antioxidant enzymes" topic_path: "general/ec-1-11-1" source: "https://en.wikipedia.org/wiki/Peroxiredoxin" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Family of antioxidant enzymes ::

::data[format=table title="Infobox protein family"]

Field	Value
Symbol	AhpC-TSA
Name	AhpC-TSA
image	Peroxiredoxin.png
caption	Structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.
Pfam	PF00578
Pfam_clan	CL0172
InterPro	IPR000866
SCOP	1prx
OPM family	131
OPM protein	1xvw
::

Peroxiredoxins (Prxs, ; HGNC root symbol PRDX) are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. The physiological importance of peroxiredoxins is indicated by their relative abundance (one of the most abundant proteins in erythrocytes after hemoglobin is peroxiredoxin 2). Their function is the reduction of peroxides, specifically hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite.

Classification

Prxs were historically divided into three (mechanistic) classes: typical 2-Cys Prxs, atypical 2-Cys Prxs, and 1-Cys Prxs. The designation of "1-Cys" and "2-Cys" Prxs was introduced in 1994 as it was noticed that, among the 22 Prx sequences known at the time, only one Cys residue was absolutely conserved; this is the residue now recognized as the (required) peroxidatic cysteine, CP. The second, semi-conserved cysteine noted at the time is the resolving cysteine, CR, which forms an intersubunit disulfide bond with CP in the widespread and abundant Prxs sometimes referred to as the "typical 2-Cys Prxs". Ultimately it was realized that the CR can reside in multiple positions in various Prx family members, leading to the addition of the "atypical 2-Cys Prx" category (Prxs for which a CR is present, but not in the "typical", originally identified position).

Family members are now recognized to fall into six classes or subgroups by sequence/structure similarity, designated as AhpC/Prx1 (essentially synonymous with "typical 2-Cys"; alkyl hydroperoxide reductase C), Prx5, Prx6, PrxQ/BCP (bacterioferritin comigratory protein), Tpx (thiol peroxidase) and AhpE (alkyl hydroperoxide reductase E) groups. It is now recognized that the existence and location of CR across all 6 groups is heterogeneous. Thus, even though the "1-Cys Prx" designation was originally associated with the Prx6 group based on the lack of a CR in human PrxVI, and many Prx6 group members appear not to have a CR, there are "1-Cys" members in all of the subgroups. Moreover, the CR can be located in 5 (known) locations in the structure, yielding either an intersubunit or intrasubunit disulfide bond in the oxidized protein (depending on CR location). To assist with identification of new members and the subgroup to which they belong, a searchable database (the PeroxiRedoxin classification indEX) including Prx sequences identified from GenBank (January 2008 through October 2011) was generated by bioinformatics analysis and is publicly available.

Peroxiredoxin-like

Mammals also have so-called "peroxiredoxin-like" genes (). In humans there are three with the symbols PRXL2A, PRXL2B, PRXL2C. These are actually selenium-free orthologs of selenoprotein U, where the selenocysteine found in the version in fishes and birds is replaced with cysteine. The replacement happens to result in a CxxC pattern similar to peroxiredoxin.

Catalytic cycle

The active sites of the peroxiredoxins feature a redox-active cysteine residue (the peroxidatic cysteine), which undergoes oxidization to a sulfenic acid by the peroxide substrate. Using high resolution crystal structures, a detailed catalytic cycle has been derived for Prxs, including a model for the redox-regulated oligomeric state proposed to control enzyme activity. These enzymes are inactivated by over-oxidation (also known as hyperoxidation) of the active thiol to the sulfinic acid (RSO2H). This damage can be reversed by sulfiredoxin.

Peroxiredoxins are frequently referred to as alkyl hydroperoxide reductase (AhpC) in bacteria. Other names include thiol specific antioxidant (TSA) and thioredoxin peroxidase (TPx).

Mammals express six peroxiredoxins:.

1-Cys enzymes: PRDX6 (in the Prx6 group)
2-Cys enzymes: PRDX1, PRDX2, PRDX3, PRDX4 (all four in the Prx1 group), and PRDX5 (in the Prx5 group)

Enzyme regulation

Peroxiredoxins can be regulated by phosphorylation, redox status such as sulfonation, acetylation, nitration, truncation and oligomerization states.

Function

Peroxiredoxin is reduced by thioredoxin (Trx) after reducing hydrogen peroxide (H2O2) in the following reactions:

Prx(reduced) + H2O2 → Prx(oxidized) + 2H2O
Prx(oxidized) + Trx(reduced) → Prx(reduced) + Trx(oxidized) in chemical terms, these reactions can be represented:
RSH + H2O2 → RSOH + 2H2O
RSOH + R'SH → RSSR'
RSSR' + 2 R"SH → RSH + R'SH + R"SSR"

The oxidized form of Prx is inactive in its reductase activity, but can function as a molecular chaperone, requiring the donation of electrons from reduced Trx to restore its catalytic activity.

The physiological importance of peroxiredoxins is illustrated by their relative abundance (one of the most abundant proteins in erythrocytes after hemoglobin is peroxiredoxin 2) as well as studies in knockout mice. Mice lacking peroxiredoxin 1 or 2 develop severe haemolytic anemia, and are predisposed to certain haematopoietic cancers. Peroxiredoxin 1 knockout mice have a 15% reduction in lifespan. Peroxiredoxin 6 knockout mice are viable and do not display obvious gross pathology, but are more sensitive to certain exogenous sources of oxidative stress, such as hyperoxia. Peroxiredoxin 3 (mitochondrial matrix peroxiredoxin) knockout mice are viable and do not display obvious gross pathology. Peroxiredoxins are proposed to play a role in cell signaling by regulating H2O2 levels.

Plant 2-Cys peroxiredoxins are post-translationally targeted to chloroplasts, where they protect the photosynthetic membrane against photooxidative damage. Nuclear gene expression depends on chloroplast-to-nucleus signalling and responds to photosynthetic signals, such as the acceptor availability at photosystem II and ABA.

Circadian clock

Peroxiredoxins have been implicated in the 24-hour internal circadian clock of many organisms.

References

(2017). "Multiple Functions and Regulation of Mammalian Peroxiredoxins". Annual Review of Biochemistry.
(1994). "Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes.". Proceedings of the National Academy of Sciences of the United States of America.
(May 2009). "Typical 2-Cys peroxiredoxins--structures, mechanisms and functions.". The FEBS Journal.
(March 2011). "Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis". Proteins.
(February 10, 2017). "An Atlas of Peroxiredoxins Created Using an Active Site Profile-Based Approach to Functionally Relevant Clustering of Proteins". PLOS Comput Biol.
(2015-08-01). "Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling". Trends in Biochemical Sciences.
(2011-01-01). "PREX: PeroxiRedoxin classification indEX, a database of subfamily assignments across the diverse peroxiredoxin family". Nucleic Acids Research.
"Search results (PRXL) {{!}} HUGO Gene Nomenclature Committee".
(2007). "Evolutionary dynamics of eukaryotic selenoproteomes: large selenoproteomes may associate with aquatic life and small with terrestrial life". Genome Biology.
(2004). "Reconsidering the evolution of eukaryotic selenoproteins: a novel nonmammalian family with scattered phylogenetic distribution". EMBO Reports.
(March 2007). "Reduction of 1-Cys peroxiredoxins by ascorbate changes the thiol-specific antioxidant paradigm, revealing another function of vitamin C". Proc. Natl. Acad. Sci. U.S.A..
(2016-10-04). "Peroxiredoxin Catalysis at Atomic Resolution". Structure.
(January 2003). "Structure, mechanism and regulation of peroxiredoxins". Trends Biochem. Sci..
Poole LB. (January 2005). "Bacterial defenses against oxidants: mechanistic features of cysteine-based peroxidases and their flavoprotein reductases". Arch. Biochem. Biophys..
(May 1994). "A thiol-specific antioxidant and sequence homology to various proteins of unknown function". BioFactors.
(July 2017). "Sulfonation of the resolving cysteine in human peroxiredoxin 1: A comprehensive analysis by mass spectrometry.". Free Radical Biology & Medicine.
(January 2009). "Enzymes or redox couples? The kinetics of thioredoxin and glutaredoxin reactions in a systems biology context". Biochem. J..
(July 2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature.
(August 2007). "Trends in oxidative aging theories". Free Radic. Biol. Med..
(April 2005). "Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins". Curr. Opin. Cell Biol..
(July 1997). "The plant 2-Cys peroxiredoxin BAS1 is a nuclear-encoded chloroplast protein: its expressional regulation, phylogenetic origin, and implications for its specific physiological function in plants". Plant J..
(April 1999). "Protective function of chloroplast 2-cysteine peroxiredoxin in photosynthesis. Evidence from transgenic Arabidopsis". Plant Physiol..
(August 2004). "The acceptor availability at photosystem I and ABA control nuclear expression of 2-Cys peroxiredoxin-A in Arabidopsis thaliana". Plant Cell Physiol..

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