Molecular mechanism of chromogenic substrate hydrolysis in the active site of human carboxylesterase-1
Kulakova A.M.1 , Khrenova M.G.2, Nemukhin A.V.3
1. Lomonosov Moscow State University, Department of Chemistry, Moscow, Russia 2. Lomonosov Moscow State University, Department of Chemistry, Moscow, Russia; Bach Institute of Biochemistry, Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, Russia 3. Lomonosov Moscow State University, Department of Chemistry, Moscow, Russia; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
Human carboxylesterases are involved in the protective processes of detoxification during the hydrolytic metabolism of xenobiotics. Knowledge of the molecular mechanisms of substrates hydrolysis in the enzymes active site is necessary for the rational drug design. In this work, the molecular mechanism of the hydrolysis reaction of para-nitrophenyl acetate in the active site of human carboxylesterase was determined using modern methods of molecular modeling. According to the combined method of quantum mechanics/molecular mechanics calculations, the chemical reaction occurs within four elementary steps, including two steps of the acylation stage, and two steps of the deacylation stage. All elementary steps have low energy barriers, with the gradual lowering of the intermediate energies that stimulates reaction in the forward direction. The molecular docking was used to estimate the binding constants of the enzyme-substrate complex and the dissociation constant of enzyme-product complexes. The effective kinetic parameters of the enzymatic hydrolysis in the active site of carboxylesterase are determined by numerical solution of the differential kinetic equations.
Kulakova A.M., Khrenova M.G., Nemukhin A.V. (2021) Molecular mechanism of chromogenic substrate hydrolysis in the active site of human carboxylesterase-1. Biomeditsinskaya Khimiya, 67(3), 300-305.
Kulakova A.M. et al. Molecular mechanism of chromogenic substrate hydrolysis in the active site of human carboxylesterase-1 // Biomeditsinskaya Khimiya. - 2021. - V. 67. -N 3. - P. 300-305.
Kulakova A.M. et al., "Molecular mechanism of chromogenic substrate hydrolysis in the active site of human carboxylesterase-1." Biomeditsinskaya Khimiya 67.3 (2021): 300-305.
Kulakova, A. M., Khrenova, M. G., Nemukhin, A. V. (2021). Molecular mechanism of chromogenic substrate hydrolysis in the active site of human carboxylesterase-1. Biomeditsinskaya Khimiya, 67(3), 300-305.
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