Peroxiredoxins (Prxs, ;

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root symbol ''PRDX'') are a ubiquitous

family Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Idea ...

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

s that also control

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...

-induced

peroxide In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable. The most common peroxide is hydrogen ...

levels and thereby mediate

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...

in mammalian cells. The family members in humans are

PRDX1 Peroxiredoxin-1 is a protein that in humans is encoded by the ''PRDX1'' gene. Function This gene encodes a member of the peroxiredoxin family of antioxidant enzymes, which reduce hydrogen peroxide and alkyl hydroperoxides. The encoded protein ...

, 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, C_P. The second, semi-conserved cysteine noted at the time is the resolving cysteine, C_R, which forms an intersubunit disulfide bond with C_P in the widespread and abundant Prxs sometimes referred to as the "typical 2-Cys Prxs". Ultimately it was realized that the C_R 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 C_R is present, but not in the "typical", originally identified position). Family members are now recognized to fall into six classes or subgroups, designated as Prx1 (essentially synonymous with "typical 2-Cys"), Prx5, Prx6, PrxQ, Tpx and AhpE groups. It is now recognized that the existence and location of C_R 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 C_R in human PrxVI, and many Prx6 group members appear not to have a C_R, there are "1-Cys" members in all of the subgroups. Moreover, the C_R can be located in 5 (known) locations in the structure, yielding either an intersubunit or intrasubunit disulfide bond in the oxidized protein (depending on C_R location). To assist with identification of new members and the subgroup to which they belong, a searchable database (the

PeroxiRedoxin classification indEX PeroxiRedoxin classification indEX (PREX ) is a database of peroxiredoxins (Prxs) classified into one of six distinct subfamilies. Classification relies on the Deacon Active Site Profiling (DASP) approach that utilizes a position specific scoring ...

) including Prx sequences identified from GenBank (January 2008 through October 2011) was generated by bioinformatics analysis and is publicl
available

Catalytic cycle

The active sites of the peroxiredoxins feature a redox-active

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, s ...

residue (the peroxidatic cysteine), which undergoes oxidization to a

sulfenic acid In chemistry, a sulfenic acid is an organosulfur compound and oxoacid with the general formula . It is the first member of the family of organosulfur oxoacids, which also include sulfinic acids () and sulfonic acids (), respectively. The base me ...

by the peroxide substrate. The recycling of the sulfenic acid back to a

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

is what distinguishes the three enzyme classes. 2-Cys peroxiredoxins are reduced by

s such as thioredoxins, thioredoxin-like proteins, or possibly

glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...

, whereas the 1-Cys enzymes may be reduced by

ascorbic acid Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) a ...

or glutathione in the presence of

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-π. 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 ensymes are inactivated by over-oxidation (also known as hyperoxidation) of the active thiol to the

sulfinic acid Sulfinic acids are oxoacids of sulfur with the structure RSO(OH). In these organosulfur compounds, sulfur is pyramidal. Structure and properties Sulfinic acids RSO2H are about 1000x more acidic than the corresponding carboxylic acid RCO2H. Sul ...

(RSO₂H). This damage can be reversed by

sulfiredoxin In enzymology, a sulfiredoxin () is an enzyme that catalyzes the chemical reaction :peroxiredoxin-(S-hydroxy-S-oxocysteine) + ATP + 2 R-SH \rightleftharpoons peroxiredoxin-(S-hydroxycysteine) + ADP + phosphate + R-S-S-R The 3 substrates of this ...

. 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:

, PRDX2, PRDX3, PRDX4 (all four in the Prx1 group), and PRDX5 (in the Prx5 group)

Enzyme regulation

Peroxiredoxins can be regulated by

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

, redox status such as sulfonation,.

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opp ...

nitration In organic chemistry, nitration is a general class of chemical processes for the introduction of a nitro group into an organic compound. The term also is applied incorrectly to the different process of forming nitrate esters between alcohols an ...

, truncation and oligomerization states.

Function

Peroxiredoxin is reduced by

thioredoxin Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by ''TXN'' and '' TXN2'' genes. Loss-of-fu ...

(Trx) after reducing

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...

(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 chaperon, 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 Peroxiredoxin-2 is a protein that in humans is encoded by the PRDX2 gene. PRDX2 encodes a member of the peroxiredoxin family of antioxidant enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions ...

) as well as studies in

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mice. Mice lacking

peroxiredoxin 1 Peroxiredoxin-1 is a protein that in humans is encoded by the ''PRDX1'' gene. Function This gene encodes a member of the peroxiredoxin family of antioxidant enzymes, which reduce hydrogen peroxide and alkyl hydroperoxides. The encoded protein ...

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 A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's current solar day) ...

of many organisms..

References