Abstract
The difference in lifetime with respect to hydrolysis of two covalent syalosyl-enzyme intermediates of two difluorinated sialic acid analogues (1 and 2) bound to Trypanosoma rangeli sialidase is rationalized based on quantum mechanical calculations. The two intermediates differ only in a single functional group, acetamide in the sialidase-1 complex and hydroxyl in the sialidase-2 complex. It is shown that the acetamide group, which is also present in the natural substrate, increases the pka of a catalytic base (Asp60) through electrostatic repulsion with the carbonyl oxygen on the ligand. This oxygen is absent in 2, resulting in a less basic Asp60 residue and, hence, a longer lifetime of the silaidase-2 complex. Presumably, the lifetime of a sialidase inhibitor complex could be increased further by substituents that stabilize the negative charge on (and lowers the pAa value of) Asp60 in T. rangeli sialidase.
Original language | English (US) |
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Pages (from-to) | 14093-14095 |
Number of pages | 3 |
Journal | Journal of Physical Chemistry B |
Volume | 112 |
Issue number | 45 |
DOIs | |
State | Published - Nov 13 2008 |