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Multiple Functions and Regulation of Mammalian Peroxiredoxins
Rhee, Sue Goo,Kil, In Sup Annual Reviews 2017 Annual review of biochemistry Vol.86 No.-
<P>Peroxiredoxins (Prxs) constitute a major family of peroxidases, with mammalian cells expressing six Prx isoforms (PrxI to PrxVI). Cells produce hydrogen peroxide (H2O2) at various intracellular locations where it can serve as a signaling molecule. Given that Prxs are abundant and possess a structure that renders the cysteine (Cys) residue at the active site highly sensitive to oxidation by H2O2, the signaling function of this oxidant requires extensive and highly localized regulation. Recent findings on the reversible regulation of PrxI through phosphorylation at the centrosome and on the hyperoxidation of the Cys at the active site of PrxIII in mitochondria are described in this review as examples of such local regulation of H2O2 signaling. Moreover, their high affinity for and sensitivity to oxidation by H2O2 confer on Prxs the ability to serve as sensors and transducers of H2O2 signaling through transfer of their oxidation state to bound effector proteins.</P>
Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins
Rhee, Sue-Goo,Kang, Sang-Won,Jeong, Woo-Jin,Chang, Tong-Shin,Yang, Kap-Seok,Woo, Hyun-Ae 이화여자대학교 약학연구소 2005 藥學硏究論文集 Vol.- No.16
Hydrogen peroxide (H_(2)O_(2)) accumulates transiently In various cell types stimulated with peptide growth factors and pariicipates in receptor signaling by oxidizing the essential cysteine residues of protein tyrosine phosphatases and the lipld phosphatase PTEN. The reversible inactivation of these phosphatases by H_(2)O_(2) Is likely required to prevent futile cycles of phosphorylation-dephosphorylation of proteins and phosphoinositides. The accumulation of H_(2)O_(2) is possible even in the presence of large amounts of the antioxidant enzymes peroxlredoxin I and II in the cytosol, probably because of a built-in mechanism of peroxiredoxin inactivation that Is mediated by H_(2)O_(2) and reversed by an ATP-dependent reduction reaction catalyzed by sulfiredoxin.
Intracellular Messenger Function of Hydrogen Peroxide and its Regulation by Peroxiredoxins
Rhee, Sue Goo 이화여자대학교 세포신호전달연구센터 2007 고사리 세포신호전달 심포지움 Vol. No.9
The observation that purified yeast glutamine synthetase is rapidly inactivated in a thiol-containing buffer yet retains activity in crude extracts containing the same thiol led to our discovery of an enzyme that protects against oxidation in a thiol-containing system. This novel antioxidant enzyme was shown to reduce hydroperoxides and, more recently, peroxynitrite with the use of electrons provided by a physiological thiol like thioredoxin. It defined a family of proteins, present in organisms from all kingdoms, that was named peroxiredoxin(Prx). All Prx enzymes contain a conserved Cys residue that undergoes a cycle of peroxide-dependent oxidation and thiol-dependent reduction during catalysis. Mammalian cells express six isoforms of Prx(Prx Ⅰ to Ⅵ), which are classified into three subgroups(2-Cys, atypical 2-Cys, and 1-Cys) based on the number and position of Cys residues that participate in catalysis. The relative abundance of Prx enzymes in mammalian cells appears to protect cellular components by removing the low levels of peroxides produced as a result of normal cellular metabolism. During catalysis, the active site cysteine is occasionally overoxidized to cysteine sulfinic acid. Contrary to the general belief that oxidation to the sulfinic state is an irreversible process in cells, studies on the fate of the overoxidized Prx species revealed a mechanism by which the catalytically active thiol form is recovered. This reversible overoxidation may represent an adaptation unique to eukaryotic cells that accommodates the intracellular messenger function of H₂O₂, but experimental validation of such speculation is yet to come. Our results suggest the existence of two additional mechanisms that are responsible for temporary inactivation of Prx Ⅰ, phosphorylation of Thr 90 by cyclin B-dependent kinase Cdc2 and phosphorylation of Tyr 194.
Spatial and temporal regulatory strategies for H₂O₂-dependent signaling
Rhee, Sue Goo 이화여자대학교 세포신호전달연구센터 2009 고사리 세포신호전달 심포지움 Vol. No.11
Hydrogen peroxide(H₂O₂) is generated in all aerobic organisms as a byproduct of normal cellular processes such as mitochondrial respiration, peroxisomal lipid metabolism, and p450-dependent oxygenation. Because H₂O₂ molecules thus produced are readily converted to hydroxyl radicals that inflict oxidative damage indiscriminately on cellular components, aerobic organisms are equipped with enzymes catalase, glutathione peroxidase, and peroxiredoxin that detoxify H₂O₂. Paradoxically, many mammalian cell types deliberately produce H₂O₂ in response to a variety of extracellular stimuli and use the hazardous molecule as an intracellular messenger that mediates biological responses such as cell growth, differentiation, and gene expression. For example, stimulation of cells with PDGF or EGF induces H₂O₂ production and blockage of H₂O₂ accumulation results in an inhibition of signaling by those growth factors. It was shown that the activation of protein tyrosine kinase(PTK) following the binding of growth factors is not sufficient to induce the accumulation of phosphorylated proteins because of the opposing activity of protein tyrosine phosphatases(PTPs) and that the concomitant inactivation of PTPs by H₂O₂ is needed to maintain the state of protein phosphorylation sufficiently to trigger downstream signaling events. H₂O₂ produced in response to growth factor stimulation was shown to reversibly inactivate PTPs by selectively oxidizing their active site cysteine. It was also shown that the catalytic cysteine of PTEN, which reverses the reaction catalyzed by PI3-kinase, is a target of reversible oxidation by H₂O₂and that the PTEN inactivation governs both the accumulation of PIP3 and the activation of Akt. For H₂O₂ to serve as a signal through modification of signaling proteins, its concentration must increase rapidly above a certain threshold. Given the toxicity of H₂O₂, spatial and temporal regulatory strategies must exist to ensure that H₂O₂ production occurs only where and when needed. In my presentation, the two strategies will be discussed in terms of redox-active endosomes and phosphorylation of peroxiredoxin.
The Peroxiredoxin Story : From the Incidentals to the Fundamentals
Rhee, Sue Goo 이화여자대학교 세포신호전달연구센터 2006 고사리 세포신호전달 심포지움 Vol. No.8
The observation that purified yeast glutamine synthetase is rapidly inactivated in a thiol-containing buffer yet retains activity in crude extracts containing the same thiol led to our discovery of an enzyme that protects against oxidation in a thiol-containing system. This novel antioxidant enzyme was shown to reduce hydroperoxides and, more recently, peroxynitrite with the use of electrons provided by a physiological thiol like thioredoxin. It defined a family of proteins, present in organisms from all kingdoms, that was named peroxiredoxin(Prx). All Prx enzymes contain a conserved Cys residue that undergoes a cycle of peroxide-dependent oxidation and thiol-dependent reduction during catalysis. Mammalian cells express six isoforms of Prx(Prx Ⅰ to Ⅵ). The relative abundance of Prx enzymes appears to protect cellular components by removing the low levels of hydro peroxides and peroxinitrites produced as a result of normal cellular metabolism in the cytosol. However, cells also produce H₂O₂ for signaling purposes. The messenger function of H₂O₂ likely requires that its concentration increase rapidly above a certain threshold, a requirement that is likely met through protection of the generated H₂O₂ molecules from destruction by cytosolic Prx isoforms. Our results suggest the existence of two different mechanisms that might be responsible for temporary inactivation of Prx Ⅰ and Prx Ⅱ:(ⅰ) phosphorylation by Cdc2, which is activated at the G₂-M transition of the cell cycle, and (ⅱ) hyperoxidation of the active site cysteine to cysteine sulfinic acid, with the reverse reaction catalyzed by sulfiredoxin.