User:Arthur Migliatti/Sandbox1
From Proteopedia
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'''Thioredoxin'''(Trx) is a protein present in all organisms, from bacterias to complex beings as humans. This page will be focused on exploring the characteristics of '''Trx1''', a cytosolic form of Trx present in eukaryotes. Trx1 has an active site composed of 2 cysteines separated by 2 aminoacids (<scene name='91/911850/Trx_cys-active_site/2'>Cys32 - X - X - Cys35</scene>) which catalyses the reduction of other thiol-proteins and becomes oxidized. It is reduced back by '''[[Thioredoxin Reductase]]'''(TrxR), which, in the end, is reduced by '''NADPH'''. Together, the two proteins and NADPH form the system Trx<ref>Lu, J.; Holmgren, A. The Thioredoxin Antioxidant System. Free Radical Biology and Medicine 2014, 66, 75–87. https://doi.org/10.1016/j.freeradbiomed.2013.07.036.</ref>. As it is shown in this <scene name='91/911850/Conservation/1'>image</scene>, both Cys32 and Cys 35 were highly conserved during evolution(<font color='mediumvioletred'><b>dark pink</b></font>). One of the most important proteins that Trx reduces is '''[[Peroxiredoxin]]'''(Prx), which catalyses the reduction of Hidrogen Peroxide(H2O2) to water. Since high concentrations of H2O2 produces other potent oxidizing molecules, such as hydroxyl radical, Prx's action, and so Trx's also, are fundamental for the cell to have a redox homeostasis and to have low amount of damage. | '''Thioredoxin'''(Trx) is a protein present in all organisms, from bacterias to complex beings as humans. This page will be focused on exploring the characteristics of '''Trx1''', a cytosolic form of Trx present in eukaryotes. Trx1 has an active site composed of 2 cysteines separated by 2 aminoacids (<scene name='91/911850/Trx_cys-active_site/2'>Cys32 - X - X - Cys35</scene>) which catalyses the reduction of other thiol-proteins and becomes oxidized. It is reduced back by '''[[Thioredoxin Reductase]]'''(TrxR), which, in the end, is reduced by '''NADPH'''. Together, the two proteins and NADPH form the system Trx<ref>Lu, J.; Holmgren, A. The Thioredoxin Antioxidant System. Free Radical Biology and Medicine 2014, 66, 75–87. https://doi.org/10.1016/j.freeradbiomed.2013.07.036.</ref>. As it is shown in this <scene name='91/911850/Conservation/1'>image</scene>, both Cys32 and Cys 35 were highly conserved during evolution(<font color='mediumvioletred'><b>dark pink</b></font>). One of the most important proteins that Trx reduces is '''[[Peroxiredoxin]]'''(Prx), which catalyses the reduction of Hidrogen Peroxide(H2O2) to water. Since high concentrations of H2O2 produces other potent oxidizing molecules, such as hydroxyl radical, Prx's action, and so Trx's also, are fundamental for the cell to have a redox homeostasis and to have low amount of damage. | ||
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| - | Trx1 is a monomeric protein and weights around 12kDa. It is formed by one five-stranded beta sheets involved by 4 alpha helix, shown <scene name='91/911850/Secondary_structure/1'>here</scene>. The active site is located on a lump between betra strand 2, where Cys 35 is located, and alpha helix 2, where Cys32 is located. By being in the end of an alpha helix, Cys32 has a lower pKa, making it possible to reduce dissulfide bonds.<ref>Holmgren, A. Thioredoxin Structure and Mechanism: Conformational Changes on Oxidation of the Active-Site Sulfhydryls to a Disulfide. Structure 1995, 3 (3), 239–243. https://doi.org/10.1016/S0969-2126(01)00153-8. | ||
| - | </ref> | ||
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| - | Trx and TrxR were first discovered in 1964 in a study realized in bacteria, and were described as necessary proteins to reduce '''[[Ribonucleotide Reductase]]'''(RNR), a protein that produces deoxyribonucleotides from ribonucleotides<ref>Laurent, T. C.; Moore, E. C.; Reichard, P. ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEOTIDES. IV. ISOLATION AND CHARACTERIZATION OF THIOREDOXIN, THE HYDROGEN DONOR FROM ESCHERICHIA COLI B. J Biol Chem 1964, 239, 3436–3444. | ||
| - | </ref>. | ||
To reduce other proteins, first happens an attack from Cys32, creating an intermolecular dissulfide bond, represented <scene name='91/911850/C32_s-s_c206/1'>here</scene> between residue Cys32 from Trx1 and residue Cys206 from '''[[MsrA]]'''. After it, residue Cys35 attacks Cys32, creating a dissulfide bond between the two cysteines in Trx1's catalytic site. This is the <scene name='91/911850/Trx_cys_-_oxidized_-_diss_bond/4'>oxidized form of Trx1</scene>. | To reduce other proteins, first happens an attack from Cys32, creating an intermolecular dissulfide bond, represented <scene name='91/911850/C32_s-s_c206/1'>here</scene> between residue Cys32 from Trx1 and residue Cys206 from '''[[MsrA]]'''. After it, residue Cys35 attacks Cys32, creating a dissulfide bond between the two cysteines in Trx1's catalytic site. This is the <scene name='91/911850/Trx_cys_-_oxidized_-_diss_bond/4'>oxidized form of Trx1</scene>. | ||
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== Structure == | == Structure == | ||
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| + | Trx1 is a monomeric protein and weights around 12kDa. It is formed by one five-stranded beta sheets involved by 4 alpha helix, shown <scene name='91/911850/Secondary_structure/1'>here</scene>. The active site is located on a lump between betra strand 2, where Cys 35 is located, and alpha helix 2, where Cys32 is located. By being in the end of an alpha helix, Cys32 has a lower pKa, making it possible to reduce dissulfide bonds.<ref>Holmgren, A. Thioredoxin Structure and Mechanism: Conformational Changes on Oxidation of the Active-Site Sulfhydryls to a Disulfide. Structure 1995, 3 (3), 239–243. https://doi.org/10.1016/S0969-2126(01)00153-8. | ||
| + | </ref> | ||
== Function == | == Function == | ||
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| + | Trx and TrxR were first discovered in 1964 in a study realized in bacteria, and were described as necessary proteins to reduce '''[[Ribonucleotide Reductase]]'''(RNR), a protein that produces deoxyribonucleotides from ribonucleotides<ref>Laurent, T. C.; Moore, E. C.; Reichard, P. ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEOTIDES. IV. ISOLATION AND CHARACTERIZATION OF THIOREDOXIN, THE HYDROGEN DONOR FROM ESCHERICHIA COLI B. J Biol Chem 1964, 239, 3436–3444. | ||
| + | </ref>. | ||
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| + | Since 1964, other functions of Trx1, different than participating in cell division, were discovered, as denitrosation and transnitrosation for example. Denitrosation is the removal of NO of a protein, and Trx1 does it by being temporarily S-nitrosataded on Cys32. Aterwards, Cys35 attacks Cys32 and forms a dissulfide bond, releasing HNO/NO to the medium. On the other hand, transnitrosation is the the nitrosation of other proteins, that the Trx1 of some species can do. | ||
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| + | Although Trx1 from a great amount of organisms has only the catalytic site cysteines, the human form of Trx1 also has other <scene name='91/911850/Structural_cysteines/3'>3 structural cysteines</scene>, Cys 62, Cys 69 and Cys 73, which can act as regulators of the protein. <scene name='91/911850/Snocys69/2'>S-nitrosation of Trx on Cys69</scene> enhances its antiapoptotic function in some cases, although its not necessary for it.<ref>Tao, L.; Gao, E.; Bryan, N. S.; Qu, Y.; Liu, H.-R.; Hu, A.; Christopher, T. A.; Lopez, B. L.; Yodoi, J.; Koch, W. J.; Feelisch, M.; Ma, X. L. Cardioprotective Effects of Thioredoxin in Myocardial Ischemia and the Reperfusion Role of S-Nitrosation. Proc Natl Acad Sci U S A 2004, 101 (31), 11471–11476. https://doi.org/10.1073/pnas.0402941101.</ref>. Cys 73 has more than one function. Firstly, it is through this residue that Trx1 transnitrosate other proteins, the Trx of not all organisms are capable of doing transnitrosation. Another function is to make Trx1 a sensor of the redox state of the cell. When the cell is in a strong oxidizing state, Trx1 forms an homodimer connected by a <scene name='91/911850/Dimer/1'>dissulfide bond between the Cys73 residue of each monomer</scene>. Since Cys73 is spacially close to the active site, the formation of a dimer prevents Trx1 from interacting with other proteins and reducing them (<font color='black'><b>black</b></font> = residues Cys73, <font color='magenta'><b>pink</b></font> = active site from monomer A, <font color='orange'><b>orange</b></font> = active site from monomer B). | ||
Falar da RNR, Prx e outras proteínas que eu tenho visto que ela interage. | Falar da RNR, Prx e outras proteínas que eu tenho visto que ela interage. | ||
Revision as of 01:10, 19 June 2022
Introduction
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References
- ↑ Lu, J.; Holmgren, A. The Thioredoxin Antioxidant System. Free Radical Biology and Medicine 2014, 66, 75–87. https://doi.org/10.1016/j.freeradbiomed.2013.07.036.
- ↑ Tao, L.; Gao, E.; Bryan, N. S.; Qu, Y.; Liu, H.-R.; Hu, A.; Christopher, T. A.; Lopez, B. L.; Yodoi, J.; Koch, W. J.; Feelisch, M.; Ma, X. L. Cardioprotective Effects of Thioredoxin in Myocardial Ischemia and the Reperfusion Role of S-Nitrosation. Proc Natl Acad Sci U S A 2004, 101 (31), 11471–11476. https://doi.org/10.1073/pnas.0402941101.
- ↑ Holmgren, A. Thioredoxin Structure and Mechanism: Conformational Changes on Oxidation of the Active-Site Sulfhydryls to a Disulfide. Structure 1995, 3 (3), 239–243. https://doi.org/10.1016/S0969-2126(01)00153-8.
- ↑ Laurent, T. C.; Moore, E. C.; Reichard, P. ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEOTIDES. IV. ISOLATION AND CHARACTERIZATION OF THIOREDOXIN, THE HYDROGEN DONOR FROM ESCHERICHIA COLI B. J Biol Chem 1964, 239, 3436–3444.
- ↑ Tao, L.; Gao, E.; Bryan, N. S.; Qu, Y.; Liu, H.-R.; Hu, A.; Christopher, T. A.; Lopez, B. L.; Yodoi, J.; Koch, W. J.; Feelisch, M.; Ma, X. L. Cardioprotective Effects of Thioredoxin in Myocardial Ischemia and the Reperfusion Role of S-Nitrosation. Proc Natl Acad Sci U S A 2004, 101 (31), 11471–11476. https://doi.org/10.1073/pnas.0402941101.
