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Abstract:

The molecular basis of the hydroxylation reaction of the Cα of a C-terminal glycine catalyzed by peptidylglycine α-hydroxylating monooxygenase (PHM) was investigated using hybrid quantum-classical (QM-MM) computational techniques. We have identified the most reactive oxygenated species and presented new insights into the hydrogen abstraction (H-abstraction) mechanism operative in PHM. Our results suggest that O2 binds to CuB to generate CuB II-O2 .- followed by electron transfer (ET) from CuA to form CuB I-O2 .-. The computed potential energy profiles for the H-abstraction reaction for CuB II-O2 .-, CuB I-O 2 ., and [CuB II-OOH]+ species indicate that none of these species can be responsible for abstraction. However, the latter species can spontaneously form [CuBO] +2 (which consists of a two-unpaired-electrons [CuBO] + moiety ferromagneticaly coupled with a radical cation located over the three CuB ligands, in the quartet spin ground state) by abstracting a proton from the surrounding solvent. Both this monooxygenated species and the one obtained by reduction with ascorbate, [CuBO] +, were found to be capable of carrying out the H-abstraction; however, whereas the former abstracts the hydrogen atom concertedly with almost no activation energy, the later forms an intermediate that continues the reaction by a rebinding step. We propose that the active species in H-abstraction in PHM is probably [CuBO]+2 because it is formed exothermically and can concertedly abstract the substrate HA atom with the lower overall activation energy. Interestingly, this species resembles the active oxidant in cytochrome P450 enzymes, Compound I, suggesting that both PHM and cytochrome P450 enzymes may carry out substrate hydroxylation by using a similar mechanism. © 2006 American Chemical Society.

Registro:

Documento: Artículo
Título:The catalytic mechanism of peptidylglycine α-hydroxylating monooxygenase investigated by computer simulation
Autor:Crespo, A.; Martí, M.A.; Roitberg, A.E.; Amzel, L.M.; Estrin, D.A.
Filiación:Departamento de Quimica Inorganica, Analitica y Quimica-Fisica, INQUIMAE-CONICET, Universidad de Buenos Aires, C1428EHA Buenos Aires, Argentina
Quantum Theory Project, Department of Chemistry, University of Florida, Gainesville, FL 32611-8435, United States
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21205, United States
Palabras clave:Cytochrome P450 enzymes; Electron transfer (ET); Peptidylglycine α-hydroxylating monooxygenase (PHM); Quantum-classical (QM-MM); Activation energy; Catalysts; Computer simulation; Ground state; Hydroxylation; Positive ions; Proteins; Quantum theory; Glycerol; ascorbic acid; cytochrome P450; glycine; hydrogen; peptidylglycine alpha hydroxylating monooxygenase; proton; reactive oxygen metabolite; solvent; unclassified drug; unspecific monooxygenase; article; carboxy terminal sequence; catalysis; chemical binding; computer simulation; electron transport; energy; enthalpy; hydroxylation; quantum mechanics; reduction; Catalysis; Computer Simulation; Hydrogen; Hydroxylation; Kinetics; Mixed Function Oxygenases; Models, Molecular; Multienzyme Complexes; Oxygen; Quantum Theory; Thermodynamics
Año:2006
Volumen:128
Número:39
Página de inicio:12817
Página de fin:12828
DOI: http://dx.doi.org/10.1021/ja062876x
Título revista:Journal of the American Chemical Society
Título revista abreviado:J. Am. Chem. Soc.
ISSN:00027863
CODEN:JACSA
CAS:ascorbic acid, 134-03-2, 15421-15-5, 50-81-7; cytochrome P450, 9035-51-2; glycine, 56-40-6, 6000-43-7, 6000-44-8; hydrogen, 12385-13-6, 1333-74-0; proton, 12408-02-5, 12586-59-3; unspecific monooxygenase, 9012-80-0, 9037-52-9, 9038-14-6; Hydrogen, 1333-74-0; Mixed Function Oxygenases, 1.-; Multienzyme Complexes; Oxygen, 7782-44-7; peptidylglycine monooxygenase, 1.14.17.3
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v128_n39_p12817_Crespo

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Citas:

---------- APA ----------
Crespo, A., Martí, M.A., Roitberg, A.E., Amzel, L.M. & Estrin, D.A. (2006) . The catalytic mechanism of peptidylglycine α-hydroxylating monooxygenase investigated by computer simulation. Journal of the American Chemical Society, 128(39), 12817-12828.
http://dx.doi.org/10.1021/ja062876x
---------- CHICAGO ----------
Crespo, A., Martí, M.A., Roitberg, A.E., Amzel, L.M., Estrin, D.A. "The catalytic mechanism of peptidylglycine α-hydroxylating monooxygenase investigated by computer simulation" . Journal of the American Chemical Society 128, no. 39 (2006) : 12817-12828.
http://dx.doi.org/10.1021/ja062876x
---------- MLA ----------
Crespo, A., Martí, M.A., Roitberg, A.E., Amzel, L.M., Estrin, D.A. "The catalytic mechanism of peptidylglycine α-hydroxylating monooxygenase investigated by computer simulation" . Journal of the American Chemical Society, vol. 128, no. 39, 2006, pp. 12817-12828.
http://dx.doi.org/10.1021/ja062876x
---------- VANCOUVER ----------
Crespo, A., Martí, M.A., Roitberg, A.E., Amzel, L.M., Estrin, D.A. The catalytic mechanism of peptidylglycine α-hydroxylating monooxygenase investigated by computer simulation. J. Am. Chem. Soc. 2006;128(39):12817-12828.
http://dx.doi.org/10.1021/ja062876x