Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration
Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinat...
Guardado en:
| Autores principales: | , , , , , , |
|---|---|
| Formato: | JOUR |
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno |
| Aporte de: |
| id |
todo:paper_00039861_v507_n2_p304_Moreno |
|---|---|
| record_format |
dspace |
| spelling |
todo:paper_00039861_v507_n2_p304_Moreno2023-10-03T13:57:04Z Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration Moreno, D.M. Martí, M.A. De Biase, P.M. Estrin, D.A. Demicheli, V. Radi, R. Boechi, L. Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinated by H26, H74, H163, D159 and one -OH ion or H2O molecule. The catalytic cycle of the enzyme is a "ping-pong" mechanism involving Mn3+/Mn2+. It is known that nitration of Y34 is responsible for enzyme inactivation, and that this protein oxidative modification is found in tissues undergoing inflammatory and degenerative processes. However, the molecular basis about MnSOD tyrosine nitration affects the protein catalytic function is mostly unknown. In this work we strongly suggest, using computer simulation tools, that Y34 nitration affects protein function by restricting ligand access to the active site. In particular, deprotonation of 3-nitrotyrosine increases drastically the energetic barrier for ligand entry due to the absence of the proton. Our results for the WT and selected mutant proteins confirm that the phenolic moiety of Y34 plays a key role in assisting superoxide migration. © 2010 Elsevier Inc. All rights reserved. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:De Biase, P.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Boechi, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine |
| spellingShingle |
Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine Moreno, D.M. Martí, M.A. De Biase, P.M. Estrin, D.A. Demicheli, V. Radi, R. Boechi, L. Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| topic_facet |
Enzyme inactivation Free energy Ligand migration Manganese superoxide dismutase MnSOD Molecular dynamics MSMD Multiple steered molecular dynamics Tyrosine nitration 3 nitrotyrosine manganese superoxide dismutase superoxide article computer simulation enzyme active site enzyme inactivation nitration priority journal protein function proton transport Catalytic Domain Enzyme Activation Humans Molecular Dynamics Simulation Mutation Nitro Compounds Superoxide Dismutase Superoxides Thermodynamics Tyrosine |
| description |
Manganese Superoxide Dismutase (MnSOD) is an essential mitochondrial antioxidant enzyme that protects organisms against oxidative damage, dismutating superoxide radical (O2-) into H2O2 and O2. The active site of the protein presents a Mn ion in a distorted trigonal-bipyramidal environment, coordinated by H26, H74, H163, D159 and one -OH ion or H2O molecule. The catalytic cycle of the enzyme is a "ping-pong" mechanism involving Mn3+/Mn2+. It is known that nitration of Y34 is responsible for enzyme inactivation, and that this protein oxidative modification is found in tissues undergoing inflammatory and degenerative processes. However, the molecular basis about MnSOD tyrosine nitration affects the protein catalytic function is mostly unknown. In this work we strongly suggest, using computer simulation tools, that Y34 nitration affects protein function by restricting ligand access to the active site. In particular, deprotonation of 3-nitrotyrosine increases drastically the energetic barrier for ligand entry due to the absence of the proton. Our results for the WT and selected mutant proteins confirm that the phenolic moiety of Y34 plays a key role in assisting superoxide migration. © 2010 Elsevier Inc. All rights reserved. |
| format |
JOUR |
| author |
Moreno, D.M. Martí, M.A. De Biase, P.M. Estrin, D.A. Demicheli, V. Radi, R. Boechi, L. |
| author_facet |
Moreno, D.M. Martí, M.A. De Biase, P.M. Estrin, D.A. Demicheli, V. Radi, R. Boechi, L. |
| author_sort |
Moreno, D.M. |
| title |
Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| title_short |
Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| title_full |
Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| title_fullStr |
Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| title_full_unstemmed |
Exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| title_sort |
exploring the molecular basis of human manganese superoxide dismutase inactivation mediated by tyrosine 34 nitration |
| url |
http://hdl.handle.net/20.500.12110/paper_00039861_v507_n2_p304_Moreno |
| work_keys_str_mv |
AT morenodm exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT martima exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT debiasepm exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT estrinda exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT demicheliv exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT radir exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration AT boechil exploringthemolecularbasisofhumanmanganesesuperoxidedismutaseinactivationmediatedbytyrosine34nitration |
| _version_ |
1807321650699436032 |