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How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase
Catechol-O-methyltransferase (COMT) degrades catecholamines, such as dopamine and epinephrine, by methylating them in the presence of a divalent metal cation (usually Mg(II)), and S-adenosyl-L-methionine. The enzymatic activity of COMT is known to be vitally dependent on the nature of the bound meta...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466255/ https://www.ncbi.nlm.nih.gov/pubmed/23056605 http://dx.doi.org/10.1371/journal.pone.0047172 |
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author | Sparta, Manuel Alexandrova, Anastassia N. |
author_facet | Sparta, Manuel Alexandrova, Anastassia N. |
author_sort | Sparta, Manuel |
collection | PubMed |
description | Catechol-O-methyltransferase (COMT) degrades catecholamines, such as dopamine and epinephrine, by methylating them in the presence of a divalent metal cation (usually Mg(II)), and S-adenosyl-L-methionine. The enzymatic activity of COMT is known to be vitally dependent on the nature of the bound metal: replacement of Mg(II) with Ca(II) leads to a complete deactivation of COMT; Fe(II) is slightly less than potent Mg(II), and Fe(III) is again an inhibitor. Considering the fairly modest role that the metal plays in the catalyzed reaction, this dependence is puzzling, and to date remains an enigma. Using a quantum mechanical / molecular mechanical dynamics method for extensive sampling of protein structure, and first principle quantum mechanical calculations for the subsequent mechanistic study, we explicate the effect of metal substitution on the rate determining step in the catalytic cycle of COMT, the methyl transfer. In full accord with experimental data, Mg(II) bound to COMT is the most potent of the studied cations and it is closely followed by Fe(II), whereas Fe(III) is unable to promote catalysis. In the case of Ca(II), a repacking of the protein binding site is observed, leading to a significant increase in the activation barrier and higher energy of reaction. Importantly, the origin of the effect of metal substitution is different for different metals: for Fe(III) it is the electronic effect, whereas in the case of Ca(II) it is instead the effect of suboptimal protein structure. |
format | Online Article Text |
id | pubmed-3466255 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34662552012-10-10 How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase Sparta, Manuel Alexandrova, Anastassia N. PLoS One Research Article Catechol-O-methyltransferase (COMT) degrades catecholamines, such as dopamine and epinephrine, by methylating them in the presence of a divalent metal cation (usually Mg(II)), and S-adenosyl-L-methionine. The enzymatic activity of COMT is known to be vitally dependent on the nature of the bound metal: replacement of Mg(II) with Ca(II) leads to a complete deactivation of COMT; Fe(II) is slightly less than potent Mg(II), and Fe(III) is again an inhibitor. Considering the fairly modest role that the metal plays in the catalyzed reaction, this dependence is puzzling, and to date remains an enigma. Using a quantum mechanical / molecular mechanical dynamics method for extensive sampling of protein structure, and first principle quantum mechanical calculations for the subsequent mechanistic study, we explicate the effect of metal substitution on the rate determining step in the catalytic cycle of COMT, the methyl transfer. In full accord with experimental data, Mg(II) bound to COMT is the most potent of the studied cations and it is closely followed by Fe(II), whereas Fe(III) is unable to promote catalysis. In the case of Ca(II), a repacking of the protein binding site is observed, leading to a significant increase in the activation barrier and higher energy of reaction. Importantly, the origin of the effect of metal substitution is different for different metals: for Fe(III) it is the electronic effect, whereas in the case of Ca(II) it is instead the effect of suboptimal protein structure. Public Library of Science 2012-10-08 /pmc/articles/PMC3466255/ /pubmed/23056605 http://dx.doi.org/10.1371/journal.pone.0047172 Text en © 2012 Sparta, Alexandrova http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sparta, Manuel Alexandrova, Anastassia N. How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title | How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title_full | How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title_fullStr | How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title_full_unstemmed | How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title_short | How Metal Substitution Affects the Enzymatic Activity of Catechol-O-Methyltransferase |
title_sort | how metal substitution affects the enzymatic activity of catechol-o-methyltransferase |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466255/ https://www.ncbi.nlm.nih.gov/pubmed/23056605 http://dx.doi.org/10.1371/journal.pone.0047172 |
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