Peroxiredoxin

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AhpC-TSA
Peroxiredoxin.png
Structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium .
Identifiers
SymbolAhpC-TSA
Pfam PF00578
Pfam clan CL0172
InterPro IPR000866
SCOP2 1prx / SCOPe / SUPFAM
OPM superfamily 131
OPM protein 1xvw
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
peroxiredoxin
Identifiers
EC no. 1.11.1.15
CAS no. 207137-51-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

Peroxiredoxins (Prxs, EC 1.11.1.15; 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. [1]

Contents

Classification

Prxs were historically divided into three (mechanistic) classes:

The designation of "1-Cys" and "2-Cys" Prxs was introduced in 1994 [2] 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, designated as Prx1 (essentially synonymous with "typical 2-Cys"), Prx5, Prx6, PrxQ, Tpx and AhpE groups. [3] [4] 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). [5] 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. [6]

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. [1] The recycling of the sulfenic acid back to a thiol is what distinguishes the three enzyme classes. 2-Cys peroxiredoxins are reduced by thiols such as thioredoxins, thioredoxin-like proteins, or possibly glutathione, whereas the 1-Cys enzymes may be reduced by ascorbic acid or glutathione in the presence of GST-π. [7] Using high resolution crystal structures, a detailed catalytic cycle has been derived for Prxs, [8] including a model for the redox-regulated oligomeric state proposed to control enzyme activity. [9] 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. [1]

Peroxiredoxins are frequently referred to as alkyl hydroperoxide reductase (AhpC) in bacteria. [10] Other names include thiol specific antioxidant (TSA) and thioredoxin peroxidase (TPx). [11]

Mammals express six peroxiredoxins:. [1]

Enzyme regulation

Peroxiredoxins can be regulated by phosphorylation, redox status such as sulfonation,. [1] acetylation, nitration, truncation and oligomerization states.

Function

Peroxiredoxin is reduced by thioredoxin (Trx) after reducing hydrogen peroxide (H2O2) in the following reactions: [1]

in chemical terms, these reactions can be represented:

The oxidized form of Prx is inactive in its reductase activity, but can function as a molecular chaperon, [12] requiring the donation of electrons from reduced Trx to restore its catalytic activity. [13]

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. [14] 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. [15] 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. [16]

Plant 2-Cys peroxiredoxins are post-translationally targeted to chloroplasts, [17] where they protect the photosynthetic membrane against photooxidative damage. [18] Nuclear gene expression depends on chloroplast-to-nucleus signalling and responds to photosynthetic signals, such as the acceptor availability at photosystem II and ABA. [19]

Circadian clock

Peroxiredoxins have been implicated in the 24-hour internal circadian clock of many organisms. [1]

See also

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol, or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. It 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, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

Thioredoxin reductases are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond.

<span class="mw-page-title-main">Thioredoxin</span> Class of reduction–oxidation proteins

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-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin is linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. Thioredoxins play a role in cell-to-cell communication.

<span class="mw-page-title-main">Glutathione disulfide</span> Chemical compound

Glutathione disulfide (GSSG) is a disulfide derived from two glutathione molecules.

<span class="mw-page-title-main">Glutaredoxin</span>

Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. In humans this oxidation repair enzyme is also known to participate in many cellular functions, including redox signaling and regulation of glucose metabolism. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, glutaredoxins are reduced by the oxidation of glutathione. Reduced glutathione is then regenerated by glutathione reductase. Together these components compose the glutathione system.

In enzymology, a sulfiredoxin is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Peroxiredoxin 1</span> Protein found in humans

Peroxiredoxin-1 is a protein that in humans is encoded by the PRDX1 gene.

<span class="mw-page-title-main">Peroxiredoxin 2</span> Protein found in humans

Peroxiredoxin-2 is a protein that in humans is encoded by the PRDX2 gene.

<span class="mw-page-title-main">PRDX6</span> Protein-coding gene in the species Homo sapiens

Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.

<span class="mw-page-title-main">PRDX5</span> Protein-coding gene in the species Homo sapiens

Peroxiredoxin-5 (PRDX5), mitochondrial is a protein that in humans is encoded by the PRDX5 gene, located on chromosome 11.

<span class="mw-page-title-main">PRDX3</span> Protein-coding gene in the species Homo sapiens

Thioredoxin-dependent peroxide reductase, mitochondrial is an enzyme that in humans is encoded by the PRDX3 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.

<span class="mw-page-title-main">PRDX4</span> Protein-coding gene in the species Homo sapiens

Peroxiredoxin-4 is a protein that in humans is encoded by the PRDX4 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.

<span class="mw-page-title-main">TXN2</span> Protein-coding gene in the species Homo sapiens

Thioredoxin, mitochondrial also known as thioredoxin-2 is a protein that in humans is encoded by the TXN2 gene on chromosome 22. This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis.

The ascorbate-glutathione cycle, sometimes Foyer-Halliwell-Asada pathway, is a metabolic pathway that detoxifies hydrogen peroxide (H2O2), a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites: ascorbate, glutathione and NADPH and the enzymes linking these metabolites.

<span class="mw-page-title-main">Ferredoxin-thioredoxin reductase</span>

Ferredoxin-thioredoxin reductase EC 1.8.7.2, systematic name ferredoxin:thioredoxin disulfide oxidoreductase, is a [4Fe-4S] protein that plays an important role in the ferredoxin/thioredoxin regulatory chain. It catalyzes the following reaction:

<span class="mw-page-title-main">Methionine sulfoxide</span> Chemical compound

Methionine sulfoxide is the organic compound with the formula CH3S(O)CH2CH2CH(NH2)CO2H. It is an amino acid that occurs naturally although it is formed post-translationally.

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

Thiol oxidoreductases are proteins that redox control by utilizing catalytic cysteine (Cys) residues for oxidation or reduction of their substrates. Examples of such proteins include thioredoxin, thioredoxin reductase, glutathione reductase, glutaredoxin, glutathione peroxidase, and peroxiredoxin.

References

  1. 1 2 3 4 5 6 7 Rhee, Sue Goo; Kil, In Sup (2017). "Multiple Functions and Regulation of Mammalian Peroxiredoxins". Annual Review of Biochemistry. 86: 749–775. doi:10.1146/annurev-biochem-060815-014431. PMID   28226215.
  2. ↑ Chae HZ, Robison K, Poole LB, Church G, Storz G, Rhee SG (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. 91 (15): 7017–7021. Bibcode:1994PNAS...91.7017C. doi: 10.1073/pnas.91.15.7017 . PMC   44329 . PMID   8041738.
  3. ↑ Nelson KJ, Knutson ST, Soito L, Klomsiri C, Poole LB, Fetrow JS (March 2011). "Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis". Proteins. 97 (3): 947–964. doi:10.1002/prot.22936. PMC   3065352 . PMID   21287625.
  4. ↑ Harper AF, Leuthaeuser JB, Babbitt PC, Morris JH, Ferrin TE, Poole LB, Fetrow JS (February 10, 2017). "An Atlas of Peroxiredoxins Created Using an Active Site Profile-Based Approach to Functionally Relevant Clustering of Proteins". PLOS Comput Biol. 13 (2): e1005284. Bibcode:2017PLSCB..13E5284H. doi: 10.1371/journal.pcbi.1005284 . PMC   5302317 . PMID   28187133.
  5. ↑ Perkins, Arden; Nelson, Kimberly J.; Parsonage, Derek; Poole, Leslie B.; Karplus, P. Andrew (2015-08-01). "Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling". Trends in Biochemical Sciences. 40 (8): 435–445. doi:10.1016/j.tibs.2015.05.001. ISSN   0968-0004. PMC   4509974 . PMID   26067716.
  6. ↑ Soito, Laura; Williamson, Chris; Knutson, Stacy T.; Fetrow, Jacquelyn S.; Poole, Leslie B.; Nelson, Kimberly J. (2011-01-01). "PREX: PeroxiRedoxin classification indEX, a database of subfamily assignments across the diverse peroxiredoxin family". Nucleic Acids Research. 39 (Database issue): D332–337. doi:10.1093/nar/gkq1060. ISSN   1362-4962. PMC   3013668 . PMID   21036863.
  7. ↑ Monteiro G, Horta BB, Pimenta DC, Augusto O, Netto LE (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. 104 (12): 4886–91. Bibcode:2007PNAS..104.4886M. doi: 10.1073/pnas.0700481104 . PMC   1829234 . PMID   17360337.
  8. ↑ Perkins, Arden; Parsonage, Derek; Nelson, Kimberly J.; Ogba, O. Maduka; Cheong, Paul Ha-Yeon; Poole, Leslie B.; Karplus, P. Andrew (2016-10-04). "Peroxiredoxin Catalysis at Atomic Resolution". Structure. 24 (10): 1668–1678. doi:10.1016/j.str.2016.07.012. ISSN   1878-4186. PMC   5241139 . PMID   27594682.
  9. ↑ Wood ZA, Schröder E, Robin Harris J, Poole LB (January 2003). "Structure, mechanism and regulation of peroxiredoxins". Trends Biochem. Sci. 28 (1): 32–40. doi:10.1016/S0968-0004(02)00003-8. PMID   12517450.
  10. ↑ Poole LB (January 2005). "Bacterial defenses against oxidants: mechanistic features of cysteine-based peroxidases and their flavoprotein reductases". Arch. Biochem. Biophys. 433 (1): 240–54. doi:10.1016/j.abb.2004.09.006. PMID   15581580.
  11. ↑ Chae HZ, Rhee SG (May 1994). "A thiol-specific antioxidant and sequence homology to various proteins of unknown function". BioFactors. 4 (3–4): 177–80. PMID   7916964.
  12. ↑ Wu, C; Dai, H; Yan, L; Liu, T; Cui, C; Chen, T; Li, H (July 2017). "Sulfonation of the resolving cysteine in human peroxiredoxin 1: A comprehensive analysis by mass spectrometry". Free Radical Biology & Medicine. 108: 785–792. doi:10.1016/j.freeradbiomed.2017.04.341. PMC   5564515 . PMID   28450148.
  13. ↑ Pillay CS, Hofmeyr JH, Olivier BG, Snoep JL, Rohwer JM (January 2009). "Enzymes or redox couples? The kinetics of thioredoxin and glutaredoxin reactions in a systems biology context". Biochem. J. 417 (1): 269–75. doi:10.1042/BJ20080690. PMID   18694397.
  14. ↑ Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH, Van Etten RA (July 2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature. 424 (6948): 561–5. Bibcode:2003Natur.424..561N. doi:10.1038/nature01819. PMID   12891360. S2CID   3570549.
  15. ↑ Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (August 2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID   17640558.
  16. ↑ Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS, Woo HA (April 2005). "Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins". Curr. Opin. Cell Biol. 17 (2): 183–9. doi:10.1016/j.ceb.2005.02.004. PMID   15780595.
  17. ↑ Baier M, Dietz KJ (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. 12 (1): 179–90. doi: 10.1046/j.1365-313X.1997.12010179.x . PMID   9263459.
  18. ↑ Baier M, Dietz KJ (April 1999). "Protective function of chloroplast 2-cysteine peroxiredoxin in photosynthesis. Evidence from transgenic Arabidopsis". Plant Physiol. 119 (4): 1407–14. doi:10.1104/pp.119.4.1407. PMC   32026 . PMID   10198100.
  19. ↑ Baier M, Ströher E, Dietz KJ (August 2004). "The acceptor availability at photosystem I and ABA control nuclear expression of 2-Cys peroxiredoxin-A in Arabidopsis thaliana". Plant Cell Physiol. 45 (8): 997–1006. doi: 10.1093/pcp/pch114 . PMID   15356325.
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