6533b861fe1ef96bd12c4564

RESEARCH PRODUCT

Mechanistic study of the biosynthesis of R-phenylcarbinol by acetohydroxyacid synthase enzyme using hybrid quantum mechanics/molecular mechanics simulations

Eduardo J. DelgadoIñaki TuñónRafael García-meseguerJ. Javier Ruiz-perníaOmar Alvarado

subject

0301 basic medicinechemistry.chemical_classification030102 biochemistry & molecular biologyBiophysicsSubstrate (chemistry)Molecular Dynamics SimulationBiochemistryMolecular mechanicsBenzaldehydeAcetolactate Synthase03 medical and health scienceschemistry.chemical_compoundMolecular dynamics030104 developmental biologychemistryCatalytic cycleNucleophileYlideQuantum mechanicsAtomQuantum TheoryMolecular BiologyBenzyl Alcohols

description

Abstract The biosynthesis of R-phenylacetylcarbinol (R-PAC) by the acetohydroxy acid synthase, (AHAS) is addressed by molecular dynamics simulations (MD), hybrid quantum mechanics/molecular mechanics (QM/MM), and QM/MM free energy calculations. The results show the reaction starts with the nucleophilic attack of the C2α atom of the HEThDP intermediate on the Cβ atom of the carbonyl group of benzaldehyde substrate via the formation of a transition state (TS1) with the HEThDP intermediate under 4′-aminopyrimidium (APH+) form. The calculated activation free energy for this step is 17.4 kcal mol−1 at 27 °C. From this point, the reaction continues with the abstraction of Hβ atom of the HEThDP intermediate by the Oβ atom of benzaldehyde to form the intermediate I. The reaction is completed with the cleavage of the bond C2α-C2 to form the product R-PAC and to regenerate the ylide intermediate under the APH+ form, allowing in this way to reinitiate to the catalytic cycle once more. The calculated activation barrier for this last step is 15.9 kcal mol−1 at 27 °C.

yearjournalcountryeditionlanguage
2021-04-01Archives of Biochemistry and Biophysics
https://doi.org/10.1016/j.abb.2021.108807