Catalytic Mechanism of Hyaluronate Lyase from <i>Spectrococcus pneumonia</i>: Quantum Mechanical/Molecular Mechanical
and Density Functional Theory Studies
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Abstract
Hyaluronate
lyase from <i>Spectrococcus pneumonia</i> can degrade hyaluronic
acid, which is one of the major components
in the extracellular matrix. The major functions of hyaluronan are
to regulate water balance and osmotic pressure and act as an ion-exchange
resin. It has been suggested in our previous molecular dynamics simulation
that the binding of the substrate molecule could lead to the ionization
of Y408 and protonation of H399. Followed by our recent molecular
dynamics simulation of the enzyme–substrate complex, a unified
proton abstraction and donation mechanism for this enzyme can be established
using a combined quantum mechanical and molecular mechanical approach
and density functional theory method. Y408 is shown to serve as the
general base in the proton abstraction, while general acid is the
next proton donation step. Overall, this reaction can be classified
into <i>syn</i>-elimination reaction mechanism. The neutralization
effects of C5 carboxylate group by several polar residues such as
N349 and H399 were also examined. Finally, in combination of our previous
molecular dynamics simulations, a complete catalytic cycle for the
degradation of hyaluronan tetrasaccharide catalyzed by the hyaluronate
lyase from <i>Spectrococcus pneumonia</i> is proposed