Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase

Тип документаJournal Article
Дата публикации2019-05-28
Название журналаJournal of Chemical Information and Modeling
ИздательAmerican Chemical Society
ISSN15499596, 1549960X
  • General Chemistry
  • Computer Science Applications
  • General Chemical Engineering
  • Library and Information Sciences
Краткое описание
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.
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1. Kots E.D., Khrenova M.G., Nemukhin A.V. Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase // Journal of Chemical Information and Modeling. 2018. Т. 59. № 5. С. 2299–2308.


DO - 10.1021/acs.jcim.8b00666

UR -

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 V.

PY - 2018

DA - 2018/11/15

PB - American Chemical Society (ACS)

SP - 2299-2308

IS - 5

VL - 59

SN - 1549-9596

SN - 1549-960X

ER -

BibTex |


doi = {10.1021/acs.jcim.8b00666},

url = {},

year = 2018,

month = {nov},

publisher = {American Chemical Society ({ACS})},

volume = {59},

number = {5},

pages = {2299--2308},

author = {Ekaterina D. Kots and Maria G. Khrenova and Alexander V. Nemukhin},

title = {Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase}


Kots, Ekaterina D., Maria G. Khrenova, and Alexander V. Nemukhin. “Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase.” Journal of Chemical Information and Modeling 59.5 (2018): 2299–2308. Crossref. Web.