User:Emily Joyce/Sandbox 1: Difference between revisions
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== Introduction == | == Introduction == | ||
[[Image:PtGPX5 mechanism with cys44+cys92 disulfide EJJ 5-3-2022.png|500px|right|thumb|PtGPX5 mechanism. First, Cys44 of α1-helix scavenges the peroxide, and the helix locally twists and unfolds slightly to do this. This forms the Cys44-SOH sulfenic acid intermediate. Then, α2-helix completely unfolds into a flexible loop so that Cys92 can rapidly form a disulfide bond with the oxidized Cys44 residue.]] | |||
[[Glutathione peroxidase]]s are a family of enzymes that have antioxidant properties.<ref name="Koh">PMID: 17531267</ref> It fights against oxidative stress by removing reactive oxygen species (ROS) from the cell.<ref name="Koh"/> Glutathione peroxidase (GPx) can convert hydrogen peroxide to water using glutathione (2GSH + H2O2 → GS–SG + 2H2O), and can reduce peroxide radicals to their corresponding alcohol forms.<ref> Fanucchi, M.V. Chapter 11 – Development of Antioxidant and Xenobiotic Metabolizing Enzyme Systems. The Lung: Development, Aging, and the Environment, Second Edition; Harding, R., Pinkerton, K.E.; Academic Press, 2014; 223-231.</ref> To do this, GPx utilizes glutathione, glutathione reductase, and cofactors FAD and NADPH.<ref> Higuchi, M. Wheat and Rice in Disease Prevention and Health-Benefits, risks and mechanisms of whole grains in health promotion. Elsevier; Watson, R., Preedy, V.R., Zibadi, S.; Academic Press, 2014; 547-557.</ref> Interestingly, GPx in plants typically rely on [[thioredoxin]] instead of glutathione as its electron donor to reduce ROS.<ref name="Koh"/> <ref> Burk, R.F.; Hill, K.E. Biotransformation. ''Comprehensive Toxicology'', 2010.</ref> Being able to utilize both thioredoxin and glutathione as substrates is not very common, generally speaking, but it has been seen before in both thioredoxin-dependent and glutathione-dependent antioxidant systems (for example, [[Thioredoxin Reductase]] from ''Karenia brevis'').<ref name="Koh"/>,<ref>Colon, R.; Wheater, M.; Joyce, E.J.; Ste.Marie, E.J.; Hondal, R.J.; Rein, K.S. The Marine Neurotoxin Brevetoxin (PbTx-2) Inhibits ''Karenia brevis'' and Mammalian Thioredoxin Reductases by Targeting Different Residues. J. Nat. Prod. 2021, 84 (11), 2961-2970. DOI: 10.1021/acs.jnatprod.1c00795</ref> Additionally, plants often have cysteine in their active site instead of selenocysteine found in most other GPx homologues.<ref name="Koh"/> <ref> Ursini, F.; Maiorino, M. Glutathione Peroxidases. ''Encyclopedia of Biological Chemistry'', Second Edition; 2013.</ref> Having cysteine in the active site typically reduces the catalytic efficiency of the enzyme in comparison with its selenocysteine-containing counterparts. Even though plant GPxs are slower, they can reduce wider variety of ROS, as they have lower substrate specificity.<ref name="Koh"/> <br /> | [[Glutathione peroxidase]]s are a family of enzymes that have antioxidant properties.<ref name="Koh">PMID: 17531267</ref> It fights against oxidative stress by removing reactive oxygen species (ROS) from the cell.<ref name="Koh"/> Glutathione peroxidase (GPx) can convert hydrogen peroxide to water using glutathione (2GSH + H2O2 → GS–SG + 2H2O), and can reduce peroxide radicals to their corresponding alcohol forms.<ref> Fanucchi, M.V. Chapter 11 – Development of Antioxidant and Xenobiotic Metabolizing Enzyme Systems. The Lung: Development, Aging, and the Environment, Second Edition; Harding, R., Pinkerton, K.E.; Academic Press, 2014; 223-231.</ref> To do this, GPx utilizes glutathione, glutathione reductase, and cofactors FAD and NADPH.<ref> Higuchi, M. Wheat and Rice in Disease Prevention and Health-Benefits, risks and mechanisms of whole grains in health promotion. Elsevier; Watson, R., Preedy, V.R., Zibadi, S.; Academic Press, 2014; 547-557.</ref> Interestingly, GPx in plants typically rely on [[thioredoxin]] instead of glutathione as its electron donor to reduce ROS.<ref name="Koh"/> <ref> Burk, R.F.; Hill, K.E. Biotransformation. ''Comprehensive Toxicology'', 2010.</ref> Being able to utilize both thioredoxin and glutathione as substrates is not very common, generally speaking, but it has been seen before in both thioredoxin-dependent and glutathione-dependent antioxidant systems (for example, [[Thioredoxin Reductase]] from ''Karenia brevis'').<ref name="Koh"/>,<ref>Colon, R.; Wheater, M.; Joyce, E.J.; Ste.Marie, E.J.; Hondal, R.J.; Rein, K.S. The Marine Neurotoxin Brevetoxin (PbTx-2) Inhibits ''Karenia brevis'' and Mammalian Thioredoxin Reductases by Targeting Different Residues. J. Nat. Prod. 2021, 84 (11), 2961-2970. DOI: 10.1021/acs.jnatprod.1c00795</ref> Additionally, plants often have cysteine in their active site instead of selenocysteine found in most other GPx homologues.<ref name="Koh"/> <ref> Ursini, F.; Maiorino, M. Glutathione Peroxidases. ''Encyclopedia of Biological Chemistry'', Second Edition; 2013.</ref> Having cysteine in the active site typically reduces the catalytic efficiency of the enzyme in comparison with its selenocysteine-containing counterparts. Even though plant GPxs are slower, they can reduce wider variety of ROS, as they have lower substrate specificity.<ref name="Koh"/> <br /> | ||
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This structure, [[2P5R]], is the oxidized form of glutathione peroxidase 5 from ''Populus trichocarpa x Populus deltoides'' (PtGPX5), from a paper entitled “Crystal Structures of a Poplar Thioredoxin Peroxidase that Exhibits the Structure of Glutathione Peroxidases: Insights into Redox-driven Conformational Changes”.<ref name="Koh"/>[https://pubmed.ncbi.nlm.nih.gov/17531267/] At the time of this publication, there were only six crystal structures of GPxs, all of which were mammalian.<ref name="Koh"/><ref>PMID: PMID: 6852035</ref><ref>PMID: 9180378</ref><ref>PMID: 16054503</ref>This paper was ground-breaking, as it provided the first GPx structures not from mammals. Black cottonwood poplar was chosen as the model organism because at the time, its full genome had recently been released and it had six GPX genes.<ref name="Koh"/> PtGPX5 got classified as a GPx-5, the category of GPxs which are not selenoproteins.<ref name="Koh"/><br /> | This structure, [[2P5R]], is the oxidized form of glutathione peroxidase 5 from ''Populus trichocarpa x Populus deltoides'' (PtGPX5), from a paper entitled “Crystal Structures of a Poplar Thioredoxin Peroxidase that Exhibits the Structure of Glutathione Peroxidases: Insights into Redox-driven Conformational Changes”.<ref name="Koh"/>[https://pubmed.ncbi.nlm.nih.gov/17531267/] At the time of this publication, there were only six crystal structures of GPxs, all of which were mammalian.<ref name="Koh"/><ref>PMID: PMID: 6852035</ref><ref>PMID: 9180378</ref><ref>PMID: 16054503</ref>This paper was ground-breaking, as it provided the first GPx structures not from mammals. Black cottonwood poplar was chosen as the model organism because at the time, its full genome had recently been released and it had six GPX genes.<ref name="Koh"/> PtGPX5 got classified as a GPx-5, the category of GPxs which are not selenoproteins.<ref name="Koh"/><br /> | ||
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<Structure load='2p5r' size='750' frame='true' align='left' caption='Glutathione Peroxidase 5 from poplar trees' scene='Insert optional scene name here' /> | <Structure load='2p5r' size='750' frame='true' align='left' caption='Glutathione Peroxidase 5 from poplar trees' scene='Insert optional scene name here' /> | ||
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== Summary == | == Summary == | ||
Glutathione peroxidases are part of the antioxidant network that minimizes the buildup of ROS in a cell. PtGPX5 was the seventh GPx to be crystallized and to have the structure determined.<ref name="Koh"/> Although GPxs don’t typically use thioredoxin as a substrate, this one does.<ref name="Koh"/> It is structurally similar to animal GPxs and has a thioredoxin fold. Its dimerization interface remains conserved regardless of oxidation state and of crystallization methods.<ref name="Koh"/> It was easier to crystallize PtGPX5 in the oxidized state compared to the reduced state.<ref name="Koh"/> The greatest conformational changes occur when it is switching redox states, as the α2-helix completely unfolds.<ref name="Koh"/> It becomes a flexible loop when Cys44 gets oxidized and Cy92 subsequently forms a disulfide with it.<ref name="Koh"/> | Glutathione peroxidases are part of the antioxidant network that minimizes the buildup of ROS in a cell. PtGPX5 was the seventh GPx to be crystallized and to have the structure determined.<ref name="Koh"/> Although GPxs don’t typically use thioredoxin as a substrate, this one does.<ref name="Koh"/> It is structurally similar to animal GPxs and has a thioredoxin fold. Its dimerization interface remains conserved regardless of oxidation state and of crystallization methods.<ref name="Koh"/> It was easier to crystallize PtGPX5 in the oxidized state compared to the reduced state.<ref name="Koh"/> The greatest conformational changes occur when it is switching redox states, as the α2-helix completely unfolds.<ref name="Koh"/> It becomes a flexible loop when Cys44 gets oxidized and Cy92 subsequently forms a disulfide with it.<ref name="Koh"/> | ||
