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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.


Documento: Artículo
Título:QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis
Autor:Dumas, V.G.; Defelipe, L.A.; Petruk, A.A.; Turjanski, A.G.; Marti, M.A.
Filiación:Departamento de Quimica Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, 2160, C1428EGA, Argentina
Instituto de Química Física de los Materiales Medio Ambiente y Energia (INQUIMAE), UBA-CONICET, Facl. de Ciencias Exactas y Natr., Univ. de Buenos Aires, Ciudad Univ., Intendente Güiraldes, 2160, C1428EGA, Argentina
Palabras clave: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
Página de inicio:1004
Página de fin:1021
Título revista:Proteins: Structure, Function and Bioinformatics
Título revista abreviado:Proteins Struct. Funct. Bioinformatics
CAS:carbon, 7440-44-0; cytochrome P450, 9035-51-2; tyrosine, 16870-43-2, 55520-40-6, 60-18-4; piperazinedione, 29990-68-9; Bacterial Proteins; cytochrome P-450 CYP121; Cytochrome P-450 Enzyme System; Diketopiperazines; Free Radicals; mycocyclosin; Oxidants; Solutions; Tyrosine; tyrosine radical


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---------- APA ----------
Dumas, V.G., Defelipe, L.A., Petruk, A.A., Turjanski, A.G. & Marti, M.A. (2014) . QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential Cytochrome p450 of Mycobacterium tuberculosis. Proteins: Structure, Function and Bioinformatics, 82(6), 1004-1021.
---------- CHICAGO ----------
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 Cytochrome p450 of Mycobacterium tuberculosis" . Proteins: Structure, Function and Bioinformatics 82, no. 6 (2014) : 1004-1021.
---------- MLA ----------
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 Cytochrome p450 of Mycobacterium tuberculosis" . Proteins: Structure, Function and Bioinformatics, vol. 82, no. 6, 2014, pp. 1004-1021.
---------- VANCOUVER ----------
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 Cytochrome p450 of Mycobacterium tuberculosis. Proteins Struct. Funct. Bioinformatics. 2014;82(6):1004-1021.