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QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase

Oxygenase activity of the flavin-dependent enzyme RutA is commonly associated with the formation of flavin-oxygen adducts in the enzyme active site. We report the results of quantum mechanics/molecular mechanics (QM/MM) modeling of possible reaction pathways initiated by various triplet state comple...

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Autores principales: Grigorenko, Bella, Domratcheva, Tatiana, Nemukhin, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005588/
https://www.ncbi.nlm.nih.gov/pubmed/36903648
http://dx.doi.org/10.3390/molecules28052405
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author Grigorenko, Bella
Domratcheva, Tatiana
Nemukhin, Alexander
author_facet Grigorenko, Bella
Domratcheva, Tatiana
Nemukhin, Alexander
author_sort Grigorenko, Bella
collection PubMed
description Oxygenase activity of the flavin-dependent enzyme RutA is commonly associated with the formation of flavin-oxygen adducts in the enzyme active site. We report the results of quantum mechanics/molecular mechanics (QM/MM) modeling of possible reaction pathways initiated by various triplet state complexes of the molecular oxygen with the reduced flavin mononucleotide (FMN) formed in the protein cavities. According to the calculation results, these triplet-state flavin-oxygen complexes can be located at both re-side and si-side of the isoalloxazine ring of flavin. In both cases, the dioxygen moiety is activated by electron transfer from FMN, stimulating the attack of the arising reactive oxygen species at the C4a, N5, C6, and C8 positions in the isoalloxazine ring after the switch to the singlet state potential energy surface. The reaction pathways lead to the C(4a)-peroxide, N(5)-oxide, or C(6)-hydroperoxide covalent adducts or directly to the oxidized flavin, depending on the initial position of the oxygen molecule in the protein cavities.
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spelling pubmed-100055882023-03-11 QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase Grigorenko, Bella Domratcheva, Tatiana Nemukhin, Alexander Molecules Article Oxygenase activity of the flavin-dependent enzyme RutA is commonly associated with the formation of flavin-oxygen adducts in the enzyme active site. We report the results of quantum mechanics/molecular mechanics (QM/MM) modeling of possible reaction pathways initiated by various triplet state complexes of the molecular oxygen with the reduced flavin mononucleotide (FMN) formed in the protein cavities. According to the calculation results, these triplet-state flavin-oxygen complexes can be located at both re-side and si-side of the isoalloxazine ring of flavin. In both cases, the dioxygen moiety is activated by electron transfer from FMN, stimulating the attack of the arising reactive oxygen species at the C4a, N5, C6, and C8 positions in the isoalloxazine ring after the switch to the singlet state potential energy surface. The reaction pathways lead to the C(4a)-peroxide, N(5)-oxide, or C(6)-hydroperoxide covalent adducts or directly to the oxidized flavin, depending on the initial position of the oxygen molecule in the protein cavities. MDPI 2023-03-06 /pmc/articles/PMC10005588/ /pubmed/36903648 http://dx.doi.org/10.3390/molecules28052405 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grigorenko, Bella
Domratcheva, Tatiana
Nemukhin, Alexander
QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title_full QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title_fullStr QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title_full_unstemmed QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title_short QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
title_sort qm/mm modeling of the flavin functionalization in the ruta monooxygenase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005588/
https://www.ncbi.nlm.nih.gov/pubmed/36903648
http://dx.doi.org/10.3390/molecules28052405
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