Peroxiredoxin

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AhpC-TSA
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
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
peroxiredoxin
Identifiers
EC no.1.11.1.15
CAS no.207137-51-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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[edit]

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[edit]

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[edit]

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

Function[edit]

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[edit]

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

See also[edit]

References[edit]

  1. ^ a b c d e f g 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.
This article incorporates text from the public domain Pfam and InterPro: IPR000866
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