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Destroy and exploit: catalyzed removal of hydroperoxides from the endoplasmic reticulum.

Ramming T, Appenzeller-Herzog C - Int J Cell Biol (2013)

Bottom Line: Peroxidases are enzymes that reduce hydroperoxide substrates.Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated.Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.

ABSTRACT
Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and-possibly-lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.

No MeSH data available.


Superimposition of GPx7 and GPx8. Overlay of the carbon-nitrogen backbones of GPx7 (green; PDB ID 2KIJ) and GPx8 (red; PDB ID 2P31) was done using the Swiss PDB viewer software (available at http://www.expasy.org/). The close resemblance of the two three-dimensional structures is particularly appreciable in the peptide loops surrounding the active site Cys (CP). The ESP retention signal (KEDL motif) and the location of the transmembrane domain (TMD) of GPx8 (not part of the crystal structure) are indicated.
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fig3: Superimposition of GPx7 and GPx8. Overlay of the carbon-nitrogen backbones of GPx7 (green; PDB ID 2KIJ) and GPx8 (red; PDB ID 2P31) was done using the Swiss PDB viewer software (available at http://www.expasy.org/). The close resemblance of the two three-dimensional structures is particularly appreciable in the peptide loops surrounding the active site Cys (CP). The ESP retention signal (KEDL motif) and the location of the transmembrane domain (TMD) of GPx8 (not part of the crystal structure) are indicated.

Mentions: Whereas no other peroxide substrate besides H2O2 has been documented for GPx8 yet, GPx7 (also known as nonselenocysteine containing phospholipid hydroperoxide glutathione peroxidase, NPGPx) can efficiently react with phospholipid hydroperoxides in vitro (k > 103 M−1 s−1, Table 1) [86]. Although speculative at present, we consider it possible that also in its native context, GPx7 can reduce lipid peroxidation products in the luminal leaflet of the ER membrane. As to GPx8, which largely shares the active site architecture with GPx7 (Figure 3), the short linker between the transmembrane anchor and the catalytic domain might not confer enough flexibility for the active site to interact with the lipid bilayer. Accordingly, both GPxs (together with PrxIV) could protect ER-oriented lipids against peroxidation by scavenging ER-luminal H2O2, but only soluble GPx7, in analogy to GPx4 [87], would be able to directly reverse lipid peroxidation by enzymatic reduction.


Destroy and exploit: catalyzed removal of hydroperoxides from the endoplasmic reticulum.

Ramming T, Appenzeller-Herzog C - Int J Cell Biol (2013)

Superimposition of GPx7 and GPx8. Overlay of the carbon-nitrogen backbones of GPx7 (green; PDB ID 2KIJ) and GPx8 (red; PDB ID 2P31) was done using the Swiss PDB viewer software (available at http://www.expasy.org/). The close resemblance of the two three-dimensional structures is particularly appreciable in the peptide loops surrounding the active site Cys (CP). The ESP retention signal (KEDL motif) and the location of the transmembrane domain (TMD) of GPx8 (not part of the crystal structure) are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824332&req=5

fig3: Superimposition of GPx7 and GPx8. Overlay of the carbon-nitrogen backbones of GPx7 (green; PDB ID 2KIJ) and GPx8 (red; PDB ID 2P31) was done using the Swiss PDB viewer software (available at http://www.expasy.org/). The close resemblance of the two three-dimensional structures is particularly appreciable in the peptide loops surrounding the active site Cys (CP). The ESP retention signal (KEDL motif) and the location of the transmembrane domain (TMD) of GPx8 (not part of the crystal structure) are indicated.
Mentions: Whereas no other peroxide substrate besides H2O2 has been documented for GPx8 yet, GPx7 (also known as nonselenocysteine containing phospholipid hydroperoxide glutathione peroxidase, NPGPx) can efficiently react with phospholipid hydroperoxides in vitro (k > 103 M−1 s−1, Table 1) [86]. Although speculative at present, we consider it possible that also in its native context, GPx7 can reduce lipid peroxidation products in the luminal leaflet of the ER membrane. As to GPx8, which largely shares the active site architecture with GPx7 (Figure 3), the short linker between the transmembrane anchor and the catalytic domain might not confer enough flexibility for the active site to interact with the lipid bilayer. Accordingly, both GPxs (together with PrxIV) could protect ER-oriented lipids against peroxidation by scavenging ER-luminal H2O2, but only soluble GPx7, in analogy to GPx4 [87], would be able to directly reverse lipid peroxidation by enzymatic reduction.

Bottom Line: Peroxidases are enzymes that reduce hydroperoxide substrates.Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated.Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.

ABSTRACT
Peroxidases are enzymes that reduce hydroperoxide substrates. In many cases, hydroperoxide reduction is coupled to the formation of a disulfide bond, which is transferred onto specific acceptor molecules, the so-called reducing substrates. As such, peroxidases control the spatiotemporal distribution of diffusible second messengers such as hydrogen peroxide (H2O2) and generate new disulfides. Members of two families of peroxidases, peroxiredoxins (Prxs) and glutathione peroxidases (GPxs), reside in different subcellular compartments or are secreted from cells. This review discusses the properties and physiological roles of PrxIV, GPx7, and GPx8 in the endoplasmic reticulum (ER) of higher eukaryotic cells where H2O2 and-possibly-lipid hydroperoxides are regularly produced. Different peroxide sources and reducing substrates for ER peroxidases are critically evaluated. Peroxidase-catalyzed detoxification of hydroperoxides coupled to the productive use of disulfides, for instance, in the ER-associated process of oxidative protein folding, appears to emerge as a common theme. Nonetheless, in vitro and in vivo studies have demonstrated that individual peroxidases serve specific, nonoverlapping roles in ER physiology.

No MeSH data available.