QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis

Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction me...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Dumas, V.G., Defelipe, L.A., Petruk, A.A., Turjanski, A.G., Marti, M.A.
Formato: INPR
Lenguaje:English
Materias:
Cyclo-di-tyrosine
CYP121
Cytochrome p450
Electron transfer
Molecular dynamics
Mycobacterium tuberculosis
QM/MM
Reaction mechanism
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_08873585_v_n_p_Dumas
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
id todo:paper_08873585_v_n_p_Dumas
record_format dspace
spelling todo:paper_08873585_v_n_p_Dumas2023-10-03T15:40:54Z QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis Dumas, V.G. Defelipe, L.A. Petruk, A.A. Turjanski, A.G. Marti, M.A. Cyclo-di-tyrosine CYP121 Cytochrome p450 Electron transfer Molecular dynamics Mycobacterium tuberculosis QM/MM Reaction mechanism Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C-C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes. © 2013 Wiley Periodicals, Inc. Fil:Dumas, V.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Defelipe, L.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Petruk, A.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. INPR English info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_08873585_v_n_p_Dumas
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language English
orig_language_str_mv English
topic Cyclo-di-tyrosine
CYP121
Cytochrome p450
Electron transfer
Molecular dynamics
Mycobacterium tuberculosis
QM/MM
Reaction mechanism
spellingShingle Cyclo-di-tyrosine
CYP121
Cytochrome p450
Electron transfer
Molecular dynamics
Mycobacterium tuberculosis
QM/MM
Reaction mechanism
Dumas, V.G.
Defelipe, L.A.
Petruk, A.A.
Turjanski, A.G.
Marti, M.A.
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
topic_facet Cyclo-di-tyrosine
CYP121
Cytochrome p450
Electron transfer
Molecular dynamics
Mycobacterium tuberculosis
QM/MM
Reaction mechanism
description Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C-C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also contribute to our general understanding of these type of enzymes. © 2013 Wiley Periodicals, Inc.
format INPR
author Dumas, V.G.
Defelipe, L.A.
Petruk, A.A.
Turjanski, A.G.
Marti, M.A.
author_facet Dumas, V.G.
Defelipe, L.A.
Petruk, A.A.
Turjanski, A.G.
Marti, M.A.
author_sort Dumas, V.G.
title QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
title_short QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
title_full QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
title_fullStr QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
title_full_unstemmed QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Fytochrome p450 of Mycobacterium tuberculosis
title_sort qm/mm study of the c-c coupling reaction mechanism of cyp121, an essential fytochrome p450 of mycobacterium tuberculosis
url http://hdl.handle.net/20.500.12110/paper_08873585_v_n_p_Dumas
work_keys_str_mv AT dumasvg qmmmstudyofthecccouplingreactionmechanismofcyp121anessentialfytochromep450ofmycobacteriumtuberculosis
AT defelipela qmmmstudyofthecccouplingreactionmechanismofcyp121anessentialfytochromep450ofmycobacteriumtuberculosis
AT petrukaa qmmmstudyofthecccouplingreactionmechanismofcyp121anessentialfytochromep450ofmycobacteriumtuberculosis
AT turjanskiag qmmmstudyofthecccouplingreactionmechanismofcyp121anessentialfytochromep450ofmycobacteriumtuberculosis
AT martima qmmmstudyofthecccouplingreactionmechanismofcyp121anessentialfytochromep450ofmycobacteriumtuberculosis
_version_ 1807315466799022080

Ejemplares similares