Journal article
Rationalization of the difference in lifetime of two covalent sialosyl-enzyme intermediates of Trypanosoma rangeli sialidase
The journal of physical chemistry. B, Vol.112(45), pp.14093-14095
11/13/2008
DOI: 10.1021/jp804314x
PMID: 18925775
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 pKa value of) Asp60 in T. rangeli sialidase.
Details
- Title: Subtitle
- Rationalization of the difference in lifetime of two covalent sialosyl-enzyme intermediates of Trypanosoma rangeli sialidase
- Creators
- Laura L Parker - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USAYing-Hua ChungClaudio J MargulisJan H Jensen
- Resource Type
- Journal article
- Publication Details
- The journal of physical chemistry. B, Vol.112(45), pp.14093-14095
- DOI
- 10.1021/jp804314x
- PMID
- 18925775
- NLM abbreviation
- J Phys Chem B
- ISSN
- 1520-6106
- eISSN
- 1520-5207
- Publisher
- American Chemical Society; United States
- Language
- English
- Date published
- 11/13/2008
- Academic Unit
- Chemistry
- Record Identifier
- 9983985884202771
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