Journal of Chemical Information and Modeling, volume 59, issue 5, pages 2299-2308
Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase
Publication type: Journal Article
Publication date: 2018-11-15
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.6
ISSN: 15499596, 1549960X
General Chemistry
Computer Science Applications
General Chemical Engineering
Library and Information Sciences
Abstract
We present the results of molecular modeling of conformational changes in the Y231C and F295S mutants of human aspartoacylase (hAsp), which allow us to propose a mechanism of allosteric regulation of enzyme activity of these protein variants. The hAsp enzyme hydrolyzes one of the most abundant amino acid derivatives in the brain, N-acetyl-aspartate. It is important to understand the reasons for diminishing activity of the mutated enzymes, which is crucial for Canavan disease patients bearing the mutated gene. We explore a model which suggests operation of hAsp in the dimer form with two dynamically inequivalent subunits. Large-scale molecular dynamics simulations reveal that the replacements Y231C and F295S at the periphery of the protein shift the equilibrium between hAsp conformations with the open and closed gates to the enzyme active site buried inside the protein. Application of the dynamical network analysis and the Markov state model approach allows us to strengthen this conclusion and provide a detailed description of dynamically induced structural changes of the protein. The decreased availability of the active site for substrate molecules in the mutated enzymes explains their diminishing activity observed in clinical experiments.
Citations by journals
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2
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Journal of Chemical Information and Modeling
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Journal of Chemical Information and Modeling
2 publications, 33.33%
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ACS Chemical Neuroscience
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ACS Chemical Neuroscience
1 publication, 16.67%
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Russian Chemical Bulletin
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Russian Chemical Bulletin
1 publication, 16.67%
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New Journal of Chemistry
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New Journal of Chemistry
1 publication, 16.67%
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Current Opinion in Structural Biology
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Current Opinion in Structural Biology
1 publication, 16.67%
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Citations by publishers
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3
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American Chemical Society (ACS)
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American Chemical Society (ACS)
3 publications, 50%
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Springer Nature
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Springer Nature
1 publication, 16.67%
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Royal Society of Chemistry (RSC)
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Royal Society of Chemistry (RSC)
1 publication, 16.67%
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Elsevier
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Elsevier
1 publication, 16.67%
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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. Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase // Journal of Chemical Information and Modeling. 2018. Vol. 59. No. 5. pp. 2299-2308.
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Kots E., Khrenova M. G., Nemukhin A. Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase // Journal of Chemical Information and Modeling. 2018. Vol. 59. No. 5. pp. 2299-2308.
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TY - JOUR
DO - 10.1021/acs.jcim.8b00666
UR - https://doi.org/10.1021%2Facs.jcim.8b00666
TI - Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase
T2 - Journal of Chemical Information and Modeling
AU - Kots, Ekaterina D.
AU - Khrenova, Maria G.
AU - Nemukhin, Alexander
PY - 2018
DA - 2018/11/15 00:00:00
PB - American Chemical Society (ACS)
SP - 2299-2308
IS - 5
VL - 59
SN - 1549-9596
SN - 1549-960X
ER -
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@article{2018_Kots,
author = {Ekaterina D. Kots and Maria G. Khrenova and Alexander Nemukhin},
title = {Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase},
journal = {Journal of Chemical Information and Modeling},
year = {2018},
volume = {59},
publisher = {American Chemical Society (ACS)},
month = {nov},
url = {https://doi.org/10.1021%2Facs.jcim.8b00666},
number = {5},
pages = {2299--2308},
doi = {10.1021/acs.jcim.8b00666}
}
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MLA
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Kots, Ekaterina D., et al. “Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase.” Journal of Chemical Information and Modeling, vol. 59, no. 5, Nov. 2018, pp. 2299-2308. https://doi.org/10.1021%2Facs.jcim.8b00666.
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