Journal of Physical Chemistry B, volume 121, issue 40, pages 9389-9397
Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase
Publication type: Journal Article
Publication date: 2017-09-27
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
Hydrolysis of N-acetylaspartate (NAA), one of the most concentrated metabolites in brain, catalyzed by human aspartoacylase (hAsp) shows a remarkable dependence of the reaction rate on substrate concentration. At low NAA concentrations, sigmoidal shape of kinetic curve is observed, followed by typical rate growth of the enzyme-catalyzed reaction, whereas at high NAA concentrations self-inhibition takes place. We show that this rate dependence is consistent with a molecular model, in which N-acetylaspartate appears to have three faces in the enzyme reaction, acting as activator at low concentrations, substrate at moderate concentrations, and inhibitor at high concentrations. To support this conclusion we identify binding sites of NAA at the hAsp dimer including those on the protein surface (activating sites) and at the dimer interface (inhibiting site). Using the Markov state model approach we demonstrate that population of either activating or inhibiting site shifts the equilibrium between the hAsp dimer conformations with the open and closed gates leading to the enzyme active site buried inside the protein. These conclusions are in accord with the calculated values of binding constants of NAA at the hAsp dimer, indicating that the activating site with a higher affinity to NAA should be occupied first, whereas the inhibiting site with a lower affinity to NAA should be occupied later. Application of the dynamical network analysis shows that communication pathways between the regulatory sites (activating or inhibiting) and the gates to the active site do not interfere. These considerations allow us to develop a kinetic mechanism and to derive the equation for the reaction rate covering the entire NAA concentration range. Perfect agreement between theoretical and experimental kinetic data provides strong support to the proposed catalytic model.
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Citations by publishers
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1 publication, 7.69%
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1 publication, 7.69%
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Elsevier
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Elsevier
1 publication, 7.69%
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Springer Nature
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Springer Nature
1 publication, 7.69%
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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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Khrenova M. G. et al. Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase // Journal of Physical Chemistry B. 2017. Vol. 121. No. 40. pp. 9389-9397.
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Khrenova M. G., Kots E., Varfolomeev S. D., Lushchekina S., Nemukhin A. Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase // Journal of Physical Chemistry B. 2017. Vol. 121. No. 40. pp. 9389-9397.
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TY - JOUR
DO - 10.1021/acs.jpcb.7b08759
UR - https://doi.org/10.1021%2Facs.jpcb.7b08759
TI - Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase
T2 - Journal of Physical Chemistry B
AU - Kots, Ekaterina D.
AU - Nemukhin, Alexander
AU - Khrenova, Maria G.
AU - Varfolomeev, S. D.
AU - Lushchekina, S.
PY - 2017
DA - 2017/09/27 00:00:00
PB - American Chemical Society (ACS)
SP - 9389-9397
IS - 40
VL - 121
SN - 1520-6106
SN - 1520-5207
ER -
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@article{2017_Khrenova,
author = {Ekaterina D. Kots and Alexander Nemukhin and Maria G. Khrenova and S. D. Varfolomeev and S. Lushchekina},
title = {Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase},
journal = {Journal of Physical Chemistry B},
year = {2017},
volume = {121},
publisher = {American Chemical Society (ACS)},
month = {sep},
url = {https://doi.org/10.1021%2Facs.jpcb.7b08759},
number = {40},
pages = {9389--9397},
doi = {10.1021/acs.jpcb.7b08759}
}
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Khrenova, Maria G., et al. “Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase.” Journal of Physical Chemistry B, vol. 121, no. 40, Sep. 2017, pp. 9389-9397. https://doi.org/10.1021%2Facs.jpcb.7b08759.
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