Aspartoacylase: a central nervous system enzyme. Structure, catalytic activity and regulation mechanisms

Abstract

Aspartoacylase is a key enzyme in the human central nervous system. Catalytic deficiency of aspartoacylase is associated with several neurodegenerative disorders, which accounts for the enhanced interest in description of the catalytic action and regulatory mechanisms of this enzyme. This review focuses on molecular modelling of the catalytic function of aspartoacylase and the ways of its allosteric regulation in terms of modern theoretical chemistry approaches. The conclusions based on experimental data on the structure and functions of aspartoacylase accumulated during the last 20 years and conclusions drawn from computer modelling results of the last 5 years are analyzed in detail. The bibliography includes 109 references.

Kinetic Modeling of the Blood Oxygenation Level Dependent (BOLD) Signals and Biocatalytic Reactions Observed in the Human Brain Using MRI: An Analysis of Normal and Pathological Conditions

“…Previously, we performed molecular modeling of the catalysis of N -acetylaspartate in the human brain. − Based on three-dimensional structure of the protein obtained from methods of quantum mechanics/molecular mechanics (QM/MM) using the technology of supercomputer calculations, we provided a detailed description of the catalytic cycle of enzyme and the contributions of individual polymorphic substitutions in amino acids to the catalytic activity of aspartoacylase . A free energy profile was built, the structures of transition states and labile intermediates were identified, and the rate constants of all elementary stages of the catalytic cycle were determined. All four polymorphic modifications in the human enzyme are pathogenic and significantly reduce the catalytic activity of the enzyme.…”

Kinetic model of the glutamate neuron-astrocytic system. N-acetylaspartylglutamate and glutamate carboxypeptidase

“…There is a reasonable notion of a significant role of Nacetylaspartylglutamate hydrolase enzyme -a peptidase (GCPII) that 'splits off' glutamic acid from NAAG to form free glutamate and N-acetylaspartic acid (NAA) -in the mechanism of glutamatergic system functioning. The NAA role and the mechanism of NAA hydrolysis with acetic acid and asparagic acid formation are discussed in detail in [23][24][25][26][27][28]. The molecular polymorphism of NAA-hydrolase is the basis for Canavan disease, a fairly common neuropathology.…”