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Registro Completo |
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Biblioteca(s): |
Embrapa Amazônia Oriental. |
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Data corrente: |
03/12/2019 |
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Data da última atualização: |
17/04/2020 |
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Tipo da produção científica: |
Artigo em Periódico Indexado |
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Autoria: |
CRUZ, J. N.; OLIVEIRA, M. S. de; SILVA, S. G.; SOUZA FILHO, A. P. da S.; PEREIRA, D. S.; LIMA, A. H. L. e; ANDRADE, E. H. de A. |
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Afiliação: |
Jorddy Neves Cruz, MPEG / CPATU; Mozaniel Santana de Oliveira, MPEG; Sebastião Gomes Silva, MPEG; ANTONIO PEDRO DA SILVA SOUZA FILHO, CPATU; DANIEL SANTIAGO PEREIRA, CPATU; Anderson Henrique Lima e Lima, UFPA; Eloisa Helena de Aguiar Andrade, MPEG. |
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Título: |
Insight into the Interaction Mechanism of Nicotine, NNK, and NNN with Cytochrome P450 2A13 Based on Molecular Dynamics Simulation. |
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Ano de publicação: |
2020 |
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Fonte/Imprenta: |
Journal of Chemical Information and Modeling, v. 60, n. 2, p. 766-776, Feb. 2020. |
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DOI: |
10.1021/acs.jcim.9b00741 |
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Idioma: |
Inglês |
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Conteúdo: |
Tobacco smoke contains various cancer-causing toxic substances, including nicotine and nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N?-nitrosonornicotine (NNN). The cytochrome 2A13 is involved in nicotine metabolism and in the activation of the pro-carcinogenic agents NNK and NNN, by means of ?-hydroxylation reactions. Despite the significance of cytochrome 2A13 in the biotransformation of these molecules, its conformational mechanism and the molecular basis involved in the process are not fully understood. In this study, we used molecular dynamics and principal component analysis simulations for an in-depth analysis of the essential protein motions involved in the interaction of cytochrome 2A13 with its substrates. We also evaluated the interaction of these substrates with the amino acid residues in the binding pocket of cytochrome 2A13. Furthermore, we quantified the nature of these chemical interactions from free energy calculations using the Molecular Mechanics/Generalized Born Surface Area method. The ligands remained favorably oriented toward compound I (cytochrome P450 O?FeIV state), to undergo ?-hydroxylation. The hydrogen bond with asparagine 297 was essential to maintaining the substrates in a favorable catalytic orientation. The plot of first principal motion vs second principal motion revealed that the enzyme?s interaction with nicotine and NNK involved different conformational subgroups, whereas the conformational subgroups in the interaction with NNN are more similar. These results provide new mechanistic insights into the mode of interaction of the substrates with the active site of cytochrome 2A13, in the presence of compound I, which is essential for ?-hydroxylation. MenosTobacco smoke contains various cancer-causing toxic substances, including nicotine and nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N?-nitrosonornicotine (NNN). The cytochrome 2A13 is involved in nicotine metabolism and in the activation of the pro-carcinogenic agents NNK and NNN, by means of ?-hydroxylation reactions. Despite the significance of cytochrome 2A13 in the biotransformation of these molecules, its conformational mechanism and the molecular basis involved in the process are not fully understood. In this study, we used molecular dynamics and principal component analysis simulations for an in-depth analysis of the essential protein motions involved in the interaction of cytochrome 2A13 with its substrates. We also evaluated the interaction of these substrates with the amino acid residues in the binding pocket of cytochrome 2A13. Furthermore, we quantified the nature of these chemical interactions from free energy calculations using the Molecular Mechanics/Generalized Born Surface Area method. The ligands remained favorably oriented toward compound I (cytochrome P450 O?FeIV state), to undergo ?-hydroxylation. The hydrogen bond with asparagine 297 was essential to maintaining the substrates in a favorable catalytic orientation. The plot of first principal motion vs second principal motion revealed that the enzyme?s interaction with nicotine and NNK involved different conformational subgroups, whereas the conformational subgroups in the intera... Mostrar Tudo |
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Palavras-Chave: |
Dinâmica molecular. |
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Thesagro: |
Nicotina. |
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Thesaurus Nal: |
Cytochrome P-450; Cytochromes; Molecular dynamics. |
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Categoria do assunto: |
H Saúde e Patologia |
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Marc: |
LEADER 02602naa a2200265 a 4500
001 2115801
005 2020-04-17
008 2020 bl uuuu u00u1 u #d
024 7 $a10.1021/acs.jcim.9b00741$2DOI
100 1 $aCRUZ, J. N.
245 $aInsight into the Interaction Mechanism of Nicotine, NNK, and NNN with Cytochrome P450 2A13 Based on Molecular Dynamics Simulation.$h[electronic resource]
260 $c2020
520 $aTobacco smoke contains various cancer-causing toxic substances, including nicotine and nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N?-nitrosonornicotine (NNN). The cytochrome 2A13 is involved in nicotine metabolism and in the activation of the pro-carcinogenic agents NNK and NNN, by means of ?-hydroxylation reactions. Despite the significance of cytochrome 2A13 in the biotransformation of these molecules, its conformational mechanism and the molecular basis involved in the process are not fully understood. In this study, we used molecular dynamics and principal component analysis simulations for an in-depth analysis of the essential protein motions involved in the interaction of cytochrome 2A13 with its substrates. We also evaluated the interaction of these substrates with the amino acid residues in the binding pocket of cytochrome 2A13. Furthermore, we quantified the nature of these chemical interactions from free energy calculations using the Molecular Mechanics/Generalized Born Surface Area method. The ligands remained favorably oriented toward compound I (cytochrome P450 O?FeIV state), to undergo ?-hydroxylation. The hydrogen bond with asparagine 297 was essential to maintaining the substrates in a favorable catalytic orientation. The plot of first principal motion vs second principal motion revealed that the enzyme?s interaction with nicotine and NNK involved different conformational subgroups, whereas the conformational subgroups in the interaction with NNN are more similar. These results provide new mechanistic insights into the mode of interaction of the substrates with the active site of cytochrome 2A13, in the presence of compound I, which is essential for ?-hydroxylation.
650 $aCytochrome P-450
650 $aCytochromes
650 $aMolecular dynamics
650 $aNicotina
653 $aDinâmica molecular
700 1 $aOLIVEIRA, M. S. de
700 1 $aSILVA, S. G.
700 1 $aSOUZA FILHO, A. P. da S.
700 1 $aPEREIRA, D. S.
700 1 $aLIMA, A. H. L. e
700 1 $aANDRADE, E. H. de A.
773 $tJournal of Chemical Information and Modeling$gv. 60, n. 2, p. 766-776, Feb. 2020.
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Registro original: |
Embrapa Amazônia Oriental (CPATU) |
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