Journal of Physical Chemistry B, volume 120, issue 18, pages 4221-4231
Modeling the Complete Catalytic Cycle of Aspartoacylase
Kots Ekaterina D.
1, 2
,
Lushchekina S.
2
,
VARFOLOMEEV Sergei D.
1, 2
,
Grigorenko Bella
1, 2
,
Nemukhin Alexander
1, 2
Publication type: Journal Article
Publication date: 2016-04-29
Journal:
Journal of Physical Chemistry B
Quartile SCImago
Q1
Quartile WOS
Q3
Impact factor: 3.3
ISSN: 15206106, 15205207
Materials Chemistry
Surfaces, Coatings and Films
Physical and Theoretical Chemistry
Abstract
The complete catalytic cycle of aspartoacylase (ASPA), a zinc-dependent enzyme responsible for cleavage of N-acetyl-l-aspartate, is characterized by the methods of molecular modeling. The reaction energy profile connecting the enzyme-substrate (ES) and the enzyme-product (EP) complexes is constructed by the quantum mechanics/molecular mechanics (QM/MM) method assisted by the molecular dynamics (MD) simulations with the QM/MM potentials. Starting from the crystal structure of ASPA complexed with the intermediate analogue, the minimum-energy geometry configurations and the corresponding transition states are located. The stages of substrate binding to the enzyme active site and release of the products are modeled by MD calculations with the replica-exchange umbrella sampling technique. It is shown that the first reaction steps, nucleophilic attack of a zinc-bound nucleophilic water molecule at the carbonyl carbon and the amide bond cleavage, are consistent with the glutamate-assisted mechanism hypothesized for the zinc-dependent hydrolases. The stages of formation of the products, acetate and l-aspartate, and regeneration of the enzyme are characterized for the first time. The constructed free energy diagram from the reactants to the products suggests that the enzyme regeneration, but not the nucleophilic attack of the catalytic water molecule, corresponds to the rate-determining stage of the full catalytic cycle of ASPA.
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Kots E. et al. Modeling the Complete Catalytic Cycle of Aspartoacylase // Journal of Physical Chemistry B. 2016. Vol. 120. No. 18. pp. 4221-4231.
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Kots E., Khrenova M. G., Lushchekina S., VARFOLOMEEV S. D., Grigorenko B., Nemukhin A. Modeling the Complete Catalytic Cycle of Aspartoacylase // Journal of Physical Chemistry B. 2016. Vol. 120. No. 18. pp. 4221-4231.
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TY - JOUR
DO - 10.1021/acs.jpcb.6b02542
UR - https://doi.org/10.1021%2Facs.jpcb.6b02542
TI - Modeling the Complete Catalytic Cycle of Aspartoacylase
T2 - Journal of Physical Chemistry B
AU - Kots, Ekaterina D.
AU - VARFOLOMEEV, Sergei D.
AU - Khrenova, Maria G.
AU - Lushchekina, S.
AU - Grigorenko, Bella
AU - Nemukhin, Alexander
PY - 2016
DA - 2016/04/29 00:00:00
PB - American Chemical Society (ACS)
SP - 4221-4231
IS - 18
VL - 120
SN - 1520-6106
SN - 1520-5207
ER -
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@article{2016_Kots,
author = {Ekaterina D. Kots and Sergei D. VARFOLOMEEV and Maria G. Khrenova and S. Lushchekina and Bella Grigorenko and Alexander Nemukhin},
title = {Modeling the Complete Catalytic Cycle of Aspartoacylase},
journal = {Journal of Physical Chemistry B},
year = {2016},
volume = {120},
publisher = {American Chemical Society (ACS)},
month = {apr},
url = {https://doi.org/10.1021%2Facs.jpcb.6b02542},
number = {18},
pages = {4221--4231},
doi = {10.1021/acs.jpcb.6b02542}
}
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MLA
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Kots, Ekaterina D., et al. “Modeling the Complete Catalytic Cycle of Aspartoacylase.” Journal of Physical Chemistry B, vol. 120, no. 18, Apr. 2016, pp. 4221-4231. https://doi.org/10.1021%2Facs.jpcb.6b02542.