The Role of Peroxiredoxins in Antioxidant Defense and Redox Signaling

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 5862

Special Issue Editor

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Interests: molecular systems biology; computational biology; redox signaling; oxidative stress; design principles of biomolecular reaction networks

Special Issue Information

Dear Colleagues,

Peroxiredoxins have emerged as key players in multiple facets of antioxidant protection and redox signaling, with important implications for human health. Recent research has highlighted their roles in a wide range of physiological and pathological processes, such as tumor progression and resistance, inflammation, aging, apoptosis, circadian metabolic rhythmicity, mitosis, spindle assembly, and DNA replication fidelity. However, numerous questions about their mechanisms of action and how these relate to structural features remain open. To name but a few: What structural features determine peroxiredoxin's catalytic efficiency and hyperoxidation resistance? What determines the specificity of their interactions with their numerous interactors? How is their activity regulated by covalent modifications, and what is the role of this regulation in the physiological context? Are redox relays the paradigmatic mechanism for transducing hydrogen peroxide signals? Does the operation of peroxiredoxin-mediated redox relays require scaffold proteins, and why? How do peroxiredoxins influence cells’ resistance to hydrogen peroxide? What determines their beneficial versus deleterious effects on cancer?

This Special Issue will welcome reviews and original research articles addressing these and other exciting questions regarding peroxiredoxin’s structural, biophysical, and kinetic properties, novel specific inhibitors and research methods, their mechanisms of action in vivo, and their role in human health.

Dr. Armindo Salvador
Guest Editor

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Keywords

  • peroxiredoxins
  • thiol redox systems
  • redox signaling
  • antioxidant protection
  • hydrogen peroxide
  • redox relays
  • redox biology
  • holdases
  • redox medicine
  • oxidative stress

Published Papers (4 papers)

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Research

21 pages, 703 KiB  
Article
Modelling the Decamerisation Cycle of PRDX1 and the Inhibition-like Effect on Its Peroxidase Activity
Antioxidants 2023, 12(9), 1707; https://doi.org/10.3390/antiox12091707 - 01 Sep 2023
Cited by 2 | Viewed by 735
Abstract
Peroxiredoxins play central roles in the detoxification of reactive oxygen species and have been modelled across multiple organisms using a variety of kinetic methods. However, the peroxiredoxin dimer-to-decamer transition has been underappreciated in these studies despite the 100-fold difference in activity between these [...] Read more.
Peroxiredoxins play central roles in the detoxification of reactive oxygen species and have been modelled across multiple organisms using a variety of kinetic methods. However, the peroxiredoxin dimer-to-decamer transition has been underappreciated in these studies despite the 100-fold difference in activity between these forms. This is due to the lack of available kinetics and a theoretical framework for modelling this process. Using published isothermal titration calorimetry data, we obtained association and dissociation rate constants of 0.050 µM−4·s−1 and 0.055 s−1, respectively, for the dimer–decamer transition of human PRDX1. We developed an approach that greatly reduces the number of reactions and species needed to model the peroxiredoxin decamer oxidation cycle. Using these data, we simulated horse radish peroxidase competition and NADPH-oxidation linked assays and found that the dimer–decamer transition had an inhibition-like effect on peroxidase activity. Further, we incorporated this dimer–decamer topology and kinetics into a published and validated in vivo model of PRDX2 in the erythrocyte and found that it almost perfectly reconciled experimental and simulated responses of PRDX2 oxidation state to hydrogen peroxide insult. By accounting for the dimer–decamer transition of peroxiredoxins, we were able to resolve several discrepancies between experimental data and available kinetic models. Full article
(This article belongs to the Special Issue The Role of Peroxiredoxins in Antioxidant Defense and Redox Signaling)
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18 pages, 5854 KiB  
Article
Loss of PRDX6 Aborts Proliferative and Migratory Signaling in Hepatocarcinoma Cell Lines
Antioxidants 2023, 12(6), 1153; https://doi.org/10.3390/antiox12061153 - 25 May 2023
Cited by 1 | Viewed by 1460
Abstract
Peroxiredoxin 6 (PRDX6), the only mammalian 1-Cys member of the peroxiredoxin family, has peroxidase, phospholipase A2 (PLA2), and lysophosphatidylcholine (LPC) acyltransferase (LPCAT) activities. It has been associated with tumor progression and cancer metastasis, but the mechanisms involved are not clear. We constructed an [...] Read more.
Peroxiredoxin 6 (PRDX6), the only mammalian 1-Cys member of the peroxiredoxin family, has peroxidase, phospholipase A2 (PLA2), and lysophosphatidylcholine (LPC) acyltransferase (LPCAT) activities. It has been associated with tumor progression and cancer metastasis, but the mechanisms involved are not clear. We constructed an SNU475 hepatocarcinoma cell line knockout for PRDX6 to study the processes of migration and invasiveness in these mesenchymal cells. They showed lipid peroxidation but inhibition of the NRF2 transcriptional regulator, mitochondrial dysfunction, metabolic reprogramming, an altered cytoskeleton, down-regulation of PCNA, and a diminished growth rate. LPC regulatory action was inhibited, indicating that loss of both the peroxidase and PLA2 activities of PRDX6 are involved. Upstream regulators MYC, ATF4, HNF4A, and HNF4G were activated. Despite AKT activation and GSK3β inhibition, the prosurvival pathway and the SNAI1-induced EMT program were aborted in the absence of PRDX6, as indicated by diminished migration and invasiveness, down-regulation of bottom-line markers of the EMT program, MMP2, cytoskeletal proteins, and triggering of the “cadherin switch”. These changes point to a role for PRDX6 in tumor development and metastasis, so it can be considered a candidate for antitumoral therapies. Full article
(This article belongs to the Special Issue The Role of Peroxiredoxins in Antioxidant Defense and Redox Signaling)
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11 pages, 1329 KiB  
Article
Protective Effects of H2S Donor Treatment in Experimental Colitis: A Focus on Antioxidants
Antioxidants 2023, 12(5), 1025; https://doi.org/10.3390/antiox12051025 - 28 Apr 2023
Cited by 1 | Viewed by 949
Abstract
Inflammatory bowel diseases (IBD) are chronic, inflammatory disorders of the gastrointestinal (GI) system, which have become a global disease over the past few decades. It has become increasingly clear that oxidative stress plays a role in the pathogenesis of IBD. Even though several [...] Read more.
Inflammatory bowel diseases (IBD) are chronic, inflammatory disorders of the gastrointestinal (GI) system, which have become a global disease over the past few decades. It has become increasingly clear that oxidative stress plays a role in the pathogenesis of IBD. Even though several effective therapies exist against IBD, these might have serious side effects. It has been proposed that hydrogen sulfide (H2S), as a novel gasotransmitter, has several physiological and pathological effects on the body. Our present study aimed to investigate the effects of H2S administration on antioxidant molecules in experimental rat colitis. As a model of IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used intracolonically (i.c.) to induce colitis in male Wistar–Hannover rats. Animals were orally treated (2 times/day) with H2S donor Lawesson’s reagent (LR). Our results showed that H2S administration significantly decreased the severity of inflammation in the colons. Furthermore, LR significantly suppressed the level of oxidative stress marker 3-nitrotyrosine (3-NT) and caused a significant elevation in the levels of antioxidant GSH, Prdx1, Prdx6, and the activity of SOD compared to TNBS. In conclusion, our results suggest that these antioxidants may offer potential therapeutic targets and H2S treatment through the activation of antioxidant defense mechanisms and may provide a promising strategy against IBD. Full article
(This article belongs to the Special Issue The Role of Peroxiredoxins in Antioxidant Defense and Redox Signaling)
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22 pages, 4235 KiB  
Article
Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides
Antioxidants 2023, 12(2), 408; https://doi.org/10.3390/antiox12020408 - 07 Feb 2023
Cited by 3 | Viewed by 1826
Abstract
Human peroxiredoxin 3 (HsPrx3) is a thiol-based peroxidase responsible for the reduction of most hydrogen peroxide and peroxynitrite formed in mitochondria. Mitochondrial disfunction can lead to membrane lipoperoxidation, resulting in the formation of lipid-bound fatty acid hydroperoxides (LFA-OOHs) which [...] Read more.
Human peroxiredoxin 3 (HsPrx3) is a thiol-based peroxidase responsible for the reduction of most hydrogen peroxide and peroxynitrite formed in mitochondria. Mitochondrial disfunction can lead to membrane lipoperoxidation, resulting in the formation of lipid-bound fatty acid hydroperoxides (LFA-OOHs) which can be released to become free fatty acid hydroperoxides (fFA-OOHs). Herein, we report that HsPrx3 is oxidized and hyperoxidized by fFA-OOHs including those derived from arachidonic acid and eicosapentaenoic acid peroxidation at position 15 with remarkably high rate constants of oxidation (>3.5 × 107 M−1s−1) and hyperoxidation (~2 × 107 M−1s−1). The endoperoxide-hydroperoxide PGG2, an intermediate in prostanoid synthesis, oxidized HsPrx3 with a similar rate constant, but was less effective in causing hyperoxidation. Biophysical methodologies suggest that HsPrx3 can bind hydrophobic structures. Indeed, molecular dynamic simulations allowed the identification of a hydrophobic patch near the enzyme active site that can allocate the hydroperoxide group of fFA-OOHs in close proximity to the thiolate in the peroxidatic cysteine. Simulations performed using available and herein reported kinetic data indicate that HsPrx3 should be considered a main target for mitochondrial fFA-OOHs. Finally, kinetic simulation analysis support that mitochondrial fFA-OOHs formation fluxes in the range of nM/s are expected to contribute to HsPrx3 hyperoxidation, a modification that has been detected in vivo under physiological and pathological conditions. Full article
(This article belongs to the Special Issue The Role of Peroxiredoxins in Antioxidant Defense and Redox Signaling)
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