QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome 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...
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v82_n6_p1004_Dumas http://hdl.handle.net/20.500.12110/paper_08873585_v82_n6_p1004_Dumas |
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paper:paper_08873585_v82_n6_p1004_Dumas2023-06-08T15:46:49Z QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis Dumas, Victoria Gisel Defelipe, Lucas Alfredo Petruk, Ariel Alcides Turjanski, Adrián Gustavo Martí, Marcelo Adrián Cyclo-di-tyrosine CYP121 Cytochrome p450 Electron transfer Molecular dynamics Mycobacterium tuberculosis QM/MM Reaction mechanism bacterial protein carbon cyp121 protein cytochrome P450 tyrosine unclassified drug bacterial protein cytochrome P-450 CYP121 cytochrome P450 free radical mycocyclosin oxidizing agent piperazinedione protein binding solution and solubility tyrosine radical article carbon carbon coupling reaction chemical bond complex formation computer simulation cross coupling reaction molecular dynamics Mycobacterium tuberculosis nonhuman oxidation reduction reaction priority journal quantum mechanics radical reaction reaction analysis chemistry enzymology molecular dynamics quantum theory solution and solubility thermodynamics Bacteria (microorganisms) Mycobacterium tuberculosis Bacterial Proteins Cytochrome P-450 Enzyme System Diketopiperazines Free Radicals Molecular Dynamics Simulation Mycobacterium tuberculosis Oxidants Oxidation-Reduction Protein Binding Quantum Theory Solutions Thermodynamics Tyrosine 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. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v82_n6_p1004_Dumas http://hdl.handle.net/20.500.12110/paper_08873585_v82_n6_p1004_Dumas |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Cyclo-di-tyrosine CYP121 Cytochrome p450 Electron transfer Molecular dynamics Mycobacterium tuberculosis QM/MM Reaction mechanism bacterial protein carbon cyp121 protein cytochrome P450 tyrosine unclassified drug bacterial protein cytochrome P-450 CYP121 cytochrome P450 free radical mycocyclosin oxidizing agent piperazinedione protein binding solution and solubility tyrosine radical article carbon carbon coupling reaction chemical bond complex formation computer simulation cross coupling reaction molecular dynamics Mycobacterium tuberculosis nonhuman oxidation reduction reaction priority journal quantum mechanics radical reaction reaction analysis chemistry enzymology molecular dynamics quantum theory solution and solubility thermodynamics Bacteria (microorganisms) Mycobacterium tuberculosis Bacterial Proteins Cytochrome P-450 Enzyme System Diketopiperazines Free Radicals Molecular Dynamics Simulation Mycobacterium tuberculosis Oxidants Oxidation-Reduction Protein Binding Quantum Theory Solutions Thermodynamics Tyrosine |
| spellingShingle |
Cyclo-di-tyrosine CYP121 Cytochrome p450 Electron transfer Molecular dynamics Mycobacterium tuberculosis QM/MM Reaction mechanism bacterial protein carbon cyp121 protein cytochrome P450 tyrosine unclassified drug bacterial protein cytochrome P-450 CYP121 cytochrome P450 free radical mycocyclosin oxidizing agent piperazinedione protein binding solution and solubility tyrosine radical article carbon carbon coupling reaction chemical bond complex formation computer simulation cross coupling reaction molecular dynamics Mycobacterium tuberculosis nonhuman oxidation reduction reaction priority journal quantum mechanics radical reaction reaction analysis chemistry enzymology molecular dynamics quantum theory solution and solubility thermodynamics Bacteria (microorganisms) Mycobacterium tuberculosis Bacterial Proteins Cytochrome P-450 Enzyme System Diketopiperazines Free Radicals Molecular Dynamics Simulation Mycobacterium tuberculosis Oxidants Oxidation-Reduction Protein Binding Quantum Theory Solutions Thermodynamics Tyrosine Dumas, Victoria Gisel Defelipe, Lucas Alfredo Petruk, Ariel Alcides Turjanski, Adrián Gustavo Martí, Marcelo Adrián QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| topic_facet |
Cyclo-di-tyrosine CYP121 Cytochrome p450 Electron transfer Molecular dynamics Mycobacterium tuberculosis QM/MM Reaction mechanism bacterial protein carbon cyp121 protein cytochrome P450 tyrosine unclassified drug bacterial protein cytochrome P-450 CYP121 cytochrome P450 free radical mycocyclosin oxidizing agent piperazinedione protein binding solution and solubility tyrosine radical article carbon carbon coupling reaction chemical bond complex formation computer simulation cross coupling reaction molecular dynamics Mycobacterium tuberculosis nonhuman oxidation reduction reaction priority journal quantum mechanics radical reaction reaction analysis chemistry enzymology molecular dynamics quantum theory solution and solubility thermodynamics Bacteria (microorganisms) Mycobacterium tuberculosis Bacterial Proteins Cytochrome P-450 Enzyme System Diketopiperazines Free Radicals Molecular Dynamics Simulation Mycobacterium tuberculosis Oxidants Oxidation-Reduction Protein Binding Quantum Theory Solutions Thermodynamics Tyrosine |
| 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. |
| author |
Dumas, Victoria Gisel Defelipe, Lucas Alfredo Petruk, Ariel Alcides Turjanski, Adrián Gustavo Martí, Marcelo Adrián |
| author_facet |
Dumas, Victoria Gisel Defelipe, Lucas Alfredo Petruk, Ariel Alcides Turjanski, Adrián Gustavo Martí, Marcelo Adrián |
| author_sort |
Dumas, Victoria Gisel |
| title |
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| title_short |
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| title_full |
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| title_fullStr |
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| title_full_unstemmed |
QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis |
| title_sort |
qm/mm study of the c-c coupling reaction mechanism of cyp121, an essential cytochrome p450 of mycobacterium tuberculosis |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v82_n6_p1004_Dumas http://hdl.handle.net/20.500.12110/paper_08873585_v82_n6_p1004_Dumas |
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