Publicado

2018-01-01

Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica

Rol of the near attack conformers during enantioselective acylation of (R,S)-propranolol catalysed by Candida antarctica lipase B

DOI:

https://doi.org/10.15446/rev.colomb.biote.v20n1.73652

Palabras clave:

enzimología, antagonistas adrenérgicos beta, dominio catalítico, simulación por computador. (es)
enzymology, adrenergic beta-receptor blockers, catalytic domain, computer simulation (en)

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Autores/as

  • Daniel Iván Barrera Valderrama Grupo de Bioquímica Teórica, Universidad Industrial de Santander, Colombia
  • Markus Doerr Grupo de Bioquímica Teórica, Universidad Industrial de Santander, Colombia.
  • Martha Cecilia Daza Espinosa Grupo de Bioquímica Teórica, Universidad Industrial de Santander, Colombia.

La lipasa B de Candida antarctica (CalB) se ha utilizado en la acilación quimio- y enantioselectiva del racemato (R,S)-propranolol. CalB tiene enantioselectividad moderada (E=63) por el R-propranolol. La enantioselectividad, se origina en la reacción de transferencia del grupo acilo desde la serina catalítica, acilada, al propranolol. La fase inicial de esta reacción involucra la formación de complejos de Michaelis y posteriormente conformaciones de ataque cercano. El análisis de las conformaciones de ataque cercano ha permitido en varios casos explicar el origen de la catálisis o reproducir el efecto catalítico. En este trabajo se profundiza en la comprensión la función de las conformaciones de ataque cercano en la enantioselectividad de la acilación del (R,S)-propranolol catalizada por CalB. Para lo anterior se realizó un estudio detallado de los complejos de Michaelis y de las conformaciones de ataque cercano del paso enantioselectivo de la reacción de acilación del (R,S)-propranolol utilizando un protocolo de dinámica molecular QM/MM (SCCDFTB/CHARMM) utilizando 6 distribuciones de velocidades iniciales y simulaciones de 2,5 ns. Se estudiaron 7 complejos CalB-propranolol. Los enlaces de hidrógeno del sitio activo de CalB acilada relevantes para la actividad catalítica fueron estables en todas las simulaciones. Las poblaciones de los complejos de Michaelis y de las conformaciones de ataque cercano son dependientes de la distribución de las velocidades iniciales de la dinámica molecular. La enantioselectividad moderada de CalB acilada, encontrada experimentalmente, puede ser parcialmente atribuida a la alta población de conformaciones de ataque cercano observada para el S-propranolol.

Candida antarctica lipase B (CalB) has been used for chemo- and enantioselective acylation of racemic (R,S)-propranolol, with moderate enantioselectivity (E=63) for R-propranolol. The enantioselective step in this reaction is the transfer of an acyl group from the catalytic acylated serine to propranolol. The initial phase of this reaction involves the formation of Michaelis complexes, followed by the formation of near-attack complexes. The analysis of the near-attack complexes has in several cases permitted to explain the origin of the catalysis or to reproduce the catalytic effect. The aim of this study was improve the understanding of the role of the near-attack complexes for the enantioselectivity of the acylation of (R,S)-propranolol, catalyzed by CalB. To this purpose a detailed investigation of the Michaelis and near-attack complexes of the enantioselective step of the acylation of (R,S)-propranolol using QM/MM molecular dynamics was performed. Several simulations (each 2,5 ns) with different initial velocity distributions were performed. In total seven CalB-propranolol complexes were studied. The hydrogen bonds in the active site of CalB, which are relevant for the catalytic activity, are stable in all simulations. The lifetime of the Michaelis complexes is considerably shorter than the simulation time. Conclusions: The populations of the Michaelis and near-attack complexes depend on the initial velocity distribution in the molecular dynamics simulations. The experimentally observed moderate enantioselectivity may be partially attributed to the high population of near-attack conformations of S-propranolol.

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Cómo citar

APA

Barrera Valderrama, D. I., Doerr, M. y Daza Espinosa, M. C. (2018). Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica. Revista Colombiana de Biotecnología, 20(1), 16–30. https://doi.org/10.15446/rev.colomb.biote.v20n1.73652

ACM

[1]
Barrera Valderrama, D.I., Doerr, M. y Daza Espinosa, M.C. 2018. Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica. Revista Colombiana de Biotecnología. 20, 1 (ene. 2018), 16–30. DOI:https://doi.org/10.15446/rev.colomb.biote.v20n1.73652.

ACS

(1)
Barrera Valderrama, D. I.; Doerr, M.; Daza Espinosa, M. C. Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica. Rev. colomb. biotecnol. 2018, 20, 16-30.

ABNT

BARRERA VALDERRAMA, D. I.; DOERR, M.; DAZA ESPINOSA, M. C. Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica. Revista Colombiana de Biotecnología, [S. l.], v. 20, n. 1, p. 16–30, 2018. DOI: 10.15446/rev.colomb.biote.v20n1.73652. Disponível em: https://revistas.unal.edu.co/index.php/biotecnologia/article/view/73652. Acesso em: 28 mar. 2024.

Chicago

Barrera Valderrama, Daniel Iván, Markus Doerr, y Martha Cecilia Daza Espinosa. 2018. «Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica». Revista Colombiana De Biotecnología 20 (1):16-30. https://doi.org/10.15446/rev.colomb.biote.v20n1.73652.

Harvard

Barrera Valderrama, D. I., Doerr, M. y Daza Espinosa, M. C. (2018) «Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica», Revista Colombiana de Biotecnología, 20(1), pp. 16–30. doi: 10.15446/rev.colomb.biote.v20n1.73652.

IEEE

[1]
D. I. Barrera Valderrama, M. Doerr, y M. C. Daza Espinosa, «Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica», Rev. colomb. biotecnol., vol. 20, n.º 1, pp. 16–30, ene. 2018.

MLA

Barrera Valderrama, D. I., M. Doerr, y M. C. Daza Espinosa. «Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica». Revista Colombiana de Biotecnología, vol. 20, n.º 1, enero de 2018, pp. 16-30, doi:10.15446/rev.colomb.biote.v20n1.73652.

Turabian

Barrera Valderrama, Daniel Iván, Markus Doerr, y Martha Cecilia Daza Espinosa. «Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica». Revista Colombiana de Biotecnología 20, no. 1 (enero 1, 2018): 16–30. Accedido marzo 28, 2024. https://revistas.unal.edu.co/index.php/biotecnologia/article/view/73652.

Vancouver

1.
Barrera Valderrama DI, Doerr M, Daza Espinosa MC. Función de los confórmeros de ataque cercano en la acilación enantioselectiva del (R,S)-propranolol catalizada por lipasa B de Candida antarctica. Rev. colomb. biotecnol. [Internet]. 1 de enero de 2018 [citado 28 de marzo de 2024];20(1):16-30. Disponible en: https://revistas.unal.edu.co/index.php/biotecnologia/article/view/73652

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1. Daniel I.Barrera Valderrama, Martha C. Daza, Markus Doerr. (2021). Finite-temperature effect in the O-acylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B. Journal of Molecular Graphics and Modelling, 107, p.107951. https://doi.org/10.1016/j.jmgm.2021.107951.

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