Rationalization of the difference in lifetime of two covalent sialosyl-enzyme intermediates of Trypanosoma rangeli sialidase

Laura L. Parker, Ying-Hua Chung, Claudio J. Margulis, Jan H. Jensen

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)14093-14095
Number of pages3
JournalJournal of Physical Chemistry B
Volume112
Issue number45
DOIs
StatePublished - Nov 13 2008

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