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Typical 2-Cys peroxiredoxins--structures, mechanisms and functions.

ABSTRACT: Peroxiredoxins are abundant cellular antioxidant proteins that help to control intracellular peroxide levels. These proteins may also function, in part, through an evolved sensitivity of some peroxiredoxins towards peroxide-mediated inactivation in hydrogen peroxide signaling in eukaryotes. This review summarizes recent progress in our understanding of the catalytic and regulatory mechanisms of 'typical 2-Cys' peroxiredoxins and of the biological roles played by these important enzymes in oxidative stress and nonstress-related cellular signaling. New evidence suggests localized peroxide buildup plays a role in nonstress-related signaling.

SUBMITTER: Hall A

PROVIDER: S-EPMC2747500 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Typical 2-Cys peroxiredoxins--structures, mechanisms and functions.

Hall Andrea A Karplus P A PA Poole Leslie B LB

The FEBS journal 20090324 9

Peroxiredoxins are abundant cellular antioxidant proteins that help to control intracellular peroxide levels. These proteins may also function, in part, through an evolved sensitivity of some peroxiredoxins towards peroxide-mediated inactivation in hydrogen peroxide signaling in eukaryotes. This review summarizes recent progress in our understanding of the catalytic and regulatory mechanisms of 'typical 2-Cys' peroxiredoxins and of the biological roles played by these important enzymes in oxidat ...[more]

PMID: 19476488

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Reduction of cysteine sulfinic acid in eukaryotic, typical 2-Cys peroxiredoxins by sulfiredoxin.

Project description:The eukaryotic, typical 2-Cys peroxiredoxins (Prxs) are inactivated by hyperoxidation of one of their active-site cysteine residues to cysteine sulfinic acid. This covalent modification is thought to enable hydrogen peroxide-mediated cell signaling and to act as a functional switch between a peroxidase and a high-molecular-weight chaperone. Moreover, hyperoxidation has been implicated in a variety of disease states associated with oxidative stress, including cancer and aging-associated pathologies. A repair enzyme, sulfiredoxin (Srx), reduces the sulfinic acid moiety by using an unusual ATP-dependent mechanism. In this process, the Prx molecule undergoes dramatic structural rearrangements to facilitate repair. Structural, kinetic, mutational, and mass spectrometry-based approaches have been used to dissect the molecular basis for Srx catalysis. The available data support the direct formation of Cys sulfinic acid phosphoryl ester and protein-based thiosulfinate intermediates. This review discusses the role of Srx in the reversal of Prx hyperoxidation, the questions raised concerning the reductant required for human Srx regeneration, and the deglutathionylating activity of Srx. The complex interplay between Prx hyperoxidation, other forms of Prx covalent modification, and the oligomeric state also are discussed.

| S-EPMC3110103 | biostudies-literature

Typical 2-Cys Peroxiredoxins as a Defense Mechanism against Metal-Induced Oxidative Stress in the Solitary Ascidian Ciona robusta.

Project description:Typical 2-Cys peroxiredoxins (2-Cys Prdxs) are proteins with antioxidant properties belonging to the thioredoxin peroxidase family. With their peroxidase activity, they contribute to the homeostatic control of reactive oxygen species (ROS) and, therefore, participate in various physiological functions, such as cell proliferation, differentiation, and apoptosis. Although Prdxs have been shown to be potential biomarkers for monitoring aquatic environments, minimal scientific attention has been devoted to describing their molecular architecture and function in marine invertebrates. Our study aims to clarify the protective role against stress induced by exposure to metals (Cu, Zn, and Cd) of three Prdxs (Prdx2, Prdx3, and Prdx4) in the solitary ascidian Ciona robusta, an invertebrate chordate. Here, we report a detailed pre- and post-translational regulation of the three Prdx isoforms. Data on intestinal mRNA expression, provided by qRT-PCR analyses, show a generalized increase for Prdx2, -3, and -4, which is correlated to metal accumulation. Furthermore, the increase in tissue enzyme activity observed after Zn exposure is slower than that observed with Cu and Cd. The obtained results increase our knowledge of the evolution of anti-stress proteins in invertebrates and emphasize the importance of the synthesis of Prdxs as an efficient way to face adverse environmental conditions.

| S-EPMC8772837 | biostudies-literature

Prokaryotic Peroxiredoxins Can Be Sensitive♦ : Overoxidation of 2-Cys Peroxiredoxin in Prokaryotes. Cyanobacterial 2-Cys Peroxiredoxins Sensitive to Oxidative Stress

Project description: Not available

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Novel hyperoxidation resistance motifs in 2-Cys peroxiredoxins.

Project description:2-Cys peroxiredoxins (Prxs) modulate hydrogen peroxide (H2O2)-mediated cell signaling. At high H2O2 levels, eukaryotic Prxs can be inactivated by hyperoxidation and are classified as sensitive Prxs. In contrast, prokaryotic Prxs are categorized as being resistant to hyperoxidation and lack the GGLG and C-terminal YF motifs present in the sensitive Prxs. Additional molecular determinants that account for the subtle differences in the susceptibility to hyperoxidation remain to be identified. A comparison of a new, 2.15-Å-resolution crystal structure of Prx2 in the oxidized, disulfide-bonded state with the hyperoxidized structure of Prx2 and Prx1 in complex with sulfiredoxin revealed three structural regions that rearrange during catalysis. With these regions in hand, focused sequence analyses were performed comparing sensitive and resistant Prx groups. From this combinatorial approach, we discovered two novel hyperoxidation resistance motifs, motifs A and B, which were validated using mutagenesis of sensitive human Prxs and resistant Salmonella enterica serovar Typhimurium AhpC. Introduction and removal of these motifs, respectively, resulted in drastic changes in the sensitivity to hyperoxidation with Prx1 becoming 100-fold more resistant to hyperoxidation and AhpC becoming 800-fold more sensitive to hyperoxidation. The increased sensitivity of the latter AhpC variant was also confirmed in vivo These results support the function of motifs A and B as primary drivers for tuning the sensitivity of Prxs to different levels of H2O2, thus enabling the initiation of variable signaling or antioxidant responses in cells.

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The interactome of 2-Cys peroxiredoxins in Plasmodium falciparum.

Project description:Peroxiredoxins (Prxs) are crucially involved in maintaining intracellular H2O2 homeostasis via their peroxidase activity. However, more recently, this class of proteins was found to also transmit oxidizing equivalents to selected downstream proteins, which suggests an important function of Prxs in the regulation of cellular protein redox relays. Using a pull-down assay based on mixed disulfide fishing, we characterized the thiol-dependent interactome of cytosolic Prx1a and mitochondrial Prx1m from the apicomplexan malaria parasite Plasmodium falciparum (Pf). Here, 127 cytosolic and 20 mitochondrial proteins that are components of essential cellular processes were found to interact with PfPrx1a and PfPrx1m, respectively. Notably, our data obtained with active-site mutants suggests that reducing equivalents might also be transferred from Prxs to target proteins. Initial functional analyses indicated that the interaction with Prx can strongly impact the activity of target proteins. The results provide initial insights into the interactome of Prxs at the level of a eukaryotic whole cell proteome. Furthermore, they contribute to our understanding of redox regulatory principles and thiol-dependent redox relays of Prxs in subcellular compartments.

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Overoxidation of 2-Cys peroxiredoxin in prokaryotes: cyanobacterial 2-Cys peroxiredoxins sensitive to oxidative stress.

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| S-EPMC2966063 | biostudies-literature

Differential parameters between cytosolic 2-Cys peroxiredoxins, PRDX1 and PRDX2.

Project description:Peroxiredoxins are thiol-dependent peroxidases that function in peroxide detoxification and H2 O2 induced signaling. Among the six isoforms expressed in humans, PRDX1 and PRDX2 share 97% sequence similarity, 77% sequence identity including the active site, subcellular localization (cytosolic) but they hold different biological functions albeit associated with their peroxidase activity. Using recombinant human PRDX1 and PRDX2, the kinetics of oxidation and hyperoxidation with H2 O2 and peroxynitrite were followed by intrinsic fluorescence. At pH 7.4, the peroxidatic cysteine of both isoforms reacts nearly tenfold faster with H2 O2 than with peroxynitrite, and both reactions are orders of magnitude faster than with most protein thiols. For both isoforms, the sulfenic acids formed are in turn oxidized by H2 O2 with rate constants of ca 2 × 103 M-1 s-1 and by peroxynitrous acid significantly faster. As previously observed, a crucial difference between PRDX1 and PRDX2 is on the resolution step of the catalytic cycle, the rate of disulfide formation (11 s-1 for PRDX1, 0.2 s-1 for PRDX2, independent of the oxidant) which correlates with their different sensitivity to hyperoxidation. This kinetic pause opens different pathways on redox signaling for these isoforms. The longer lifetime of PRDX2 sulfenic acid allows it to react with other protein thiols to translate the signal via an intermediate mixed disulfide (involving its peroxidatic cysteine), whereas PRDX1 continues the cycle forming disulfide involving its resolving cysteine to function as a redox relay. In addition, the presence of C83 on PRDX1 imparts a difference on peroxidase activity upon peroxynitrite exposure that needs further study.

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Polyubiquitin chains: functions, structures, and mechanisms.

Project description:Ubiquitin is a highly conserved 76-amino acid polypeptide that is found throughout the eukaryotic kingdom. The covalent conjugation of ubiquitin (often in the form of a polymer) to substrates governs a variety of biological processes ranging from proteolysis to DNA damage tolerance. The functional flexibility of this post-translational modification has its roots in the existence of a large number of ubiquitinating enzymes that catalyze the formation of distinct ubiquitin polymers, which in turn encode different signals. This review summarizes recent advances in the field with an emphasis on the non-canonical functions of polyubiquitination. We also discuss the potential mechanism of chain linkage specification as well as how structural disparity in ubiquitin polymers may be distinguished by ubiquitin receptors to translate the versatile ubiquitin signals into various cellular functions.

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A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation.

Project description:Hydrogen peroxide (H2O2) acts as a signaling messenger by triggering the reversible oxidation of redox-regulated proteins. It remains unclear how proteins can be oxidized by signaling levels of H2O2 in the presence of peroxiredoxins, which are highly efficient peroxide scavengers. Here we show that the rapid formation of disulfide bonds in cytosolic proteins is enabled, rather than competed, by cytosolic 2-Cys peroxiredoxins. Under the conditions tested, the combined deletion or depletion of cytosolic peroxiredoxins broadly frustrated H2O2-dependent protein thiol oxidation, which is the exact opposite of what would be predicted based on the assumption that H2O2 oxidizes proteins directly. We find that peroxiredoxins enable rapid and sensitive protein thiol oxidation by relaying H2O2-derived oxidizing equivalents to other proteins. Although these findings do not rule out the existence of Prx-independent H2O2 signaling mechanisms, they suggest a broader role for peroxiredoxins as sensors and transmitters of H2O2 signals than hitherto recognized.

| S-EPMC5863949 | biostudies-literature

Effect of 2-Cys Peroxiredoxins Inhibition on Redox Modifications of Bull Sperm Proteins.

Project description:Sperm peroxiredoxins (PRDXs) are moonlighting proteins which, in addition to their antioxidant activity, also act as redox signal transducers through PRDX-induced oxidative post-translational modifications of proteins (oxPTMs). Despite extensive knowledge on the antioxidant activity of PRDXs, the mechanisms related to PRDX-mediated oxPTMs are poorly understood. The present study aimed to investigate the effect of bull sperm 2-Cys PRDX inhibition by Conoidin A on changes in oxPTM levels under control and oxidative stress conditions. The results showed that a group of sperm mitochondrial (LDHAL6B, CS, ACO2, SDHA, ACAPM) and actin cytoskeleton proteins (CAPZB, ALDOA, CCIN) is oxidized due to the action of 2-Cys PRDXs under control conditions. In turn, under oxidative stress conditions, 2-Cys PRDX activity seems to be focused on antioxidant function protecting glycolytic, TCA pathway, and respiratory chain enzymes; chaperones; and sperm axonemal tubulins from oxidative damage. Interestingly, the inhibition of PRDX resulted in oxidation of a group of rate-limiting glycolytic proteins, which is known to trigger the switching of glucose metabolism from glycolysis to pentose phosphate pathway (PPP). The obtained results are expected to broaden the knowledge of the potential role of bull sperm 2-Cys in both redox signal transmission and antioxidant activity.

| S-EPMC8657687 | biostudies-literature

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