Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase

J Phys Chem B. 2017 Oct 12;121(40):9389-9397. doi: 10.1021/acs.jpcb.7b08759. Epub 2017 Sep 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / chemistry
  • Amidohydrolases / metabolism*
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemistry
  • Aspartic Acid / metabolism
  • Catalytic Domain
  • Enzyme Activators / chemistry
  • Enzyme Activators / metabolism
  • Humans
  • Hydrolysis
  • Kinetics
  • Models, Chemical
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation

Substances

  • Enzyme Activators
  • Aspartic Acid
  • N-acetylaspartate
  • Amidohydrolases
  • aspartoacylase