Biology:Peroxiredoxin

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Short description: Family of antioxidant enzymes
AhpC-TSA
Peroxiredoxin.png
Structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium.
Identifiers
SymbolAhpC-TSA
PfamPF00578
Pfam clanCL0172
InterProIPR000866
SCOP21prx / SCOPe / SUPFAM
OPM superfamily131
OPM protein1xvw
peroxiredoxin
Identifiers
EC number1.11.1.15
CAS number207137-51-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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]

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[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]

  • 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,.[1] acetylation, nitration, truncation and oligomerization states.

Function

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

  • 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,[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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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. ↑ "Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes." (in en). Proceedings of the National Academy of Sciences of the United States of America 91 (15): 7017–7021. 1994. doi:10.1073/pnas.91.15.7017. PMID 8041738. Bibcode: 1994PNAS...91.7017C. 
  3. ↑ "Analysis of the peroxiredoxin family: using active-site structure and sequence information for global classification and residue analysis". Proteins 97 (3): 947–964. March 2011. doi:10.1002/prot.22936. PMID 21287625. 
  4. ↑ "An Atlas of Peroxiredoxins Created Using an Active Site Profile-Based Approach to Functionally Relevant Clustering of Proteins". PLOS Comput Biol 13 (2): e1005284. February 10, 2017. doi:10.1371/journal.pcbi.1005284. PMID 28187133. Bibcode: 2017PLSCB..13E5284H. 
  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. 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. PMID 21036863. 
  7. ↑ "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. March 2007. doi:10.1073/pnas.0700481104. PMID 17360337. Bibcode: 2007PNAS..104.4886M. 
  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. PMID 27594682. 
  9. ↑ "Structure, mechanism and regulation of peroxiredoxins". Trends Biochem. Sci. 28 (1): 32–40. January 2003. 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. ↑ "A thiol-specific antioxidant and sequence homology to various proteins of unknown function". BioFactors 4 (3–4): 177–80. May 1994. 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. PMID 28450148. 
  13. ↑ "Enzymes or redox couples? The kinetics of thioredoxin and glutaredoxin reactions in a systems biology context". Biochem. J. 417 (1): 269–75. January 2009. doi:10.1042/BJ20080690. PMID 18694397. 
  14. ↑ "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression". Nature 424 (6948): 561–5. July 2003. doi:10.1038/nature01819. PMID 12891360. Bibcode: 2003Natur.424..561N. http://www.escholarship.org/uc/item/8m75q3ct. 
  15. ↑ "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. August 2007. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. 
  16. ↑ "Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins". Curr. Opin. Cell Biol. 17 (2): 183–9. April 2005. doi:10.1016/j.ceb.2005.02.004. PMID 15780595. 
  17. ↑ "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. July 1997. doi:10.1046/j.1365-313X.1997.12010179.x. PMID 9263459. 
  18. ↑ "Protective function of chloroplast 2-cysteine peroxiredoxin in photosynthesis. Evidence from transgenic Arabidopsis". Plant Physiol. 119 (4): 1407–14. April 1999. doi:10.1104/pp.119.4.1407. PMID 10198100. 
  19. ↑ "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. August 2004. doi:10.1093/pcp/pch114. PMID 15356325. 
This article incorporates text from the public domain Pfam and InterPro: IPR000866



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