Abstract
Glutamate racemases (GR) catalyze the racemization of d- and l-glutamate and are targets for the development of antibiotics. We demonstrate that GR from the periodontal pathogen Fusobacterium nucleatum (FnGR) catalyzes the racemization of d-homocysteic acid (d-HCA), while l-HCA is a poor substrate. This enantioselectivity arises because l-HCA perturbs FnGR's monomer–dimer equilibrium toward inactive monomer. The inhibitory effect of l-HCA may be overcome by increasing the total FnGR concentration or by adding glutamate, but not by blocking access to the active site through site-directed mutagenesis, suggesting that l-HCA binds at an allosteric site. This phenomenon is also exhibited by GR from Bacillus subtilis, suggesting that enantiospecific, “substrate”-induced dissociation of oligomers to form inactive monomers may furnish a new inhibition strategy.
| Original language | English |
|---|---|
| Pages (from-to) | 3399-3413 |
| Number of pages | 15 |
| Journal | FEBS Letters |
| Volume | 592 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - Oct 2018 |
Bibliographical note
Funding Information:We thank Dr. Jan Rainey (Dalhousie University) for use of his fluorescence spectrophotometer. This work was supported by a Health Research Grant and a Scotia Support Grant from the Nova Scotia Health Research Foundation, a Discovery Grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada (grant no. RGPIN-2016-05083), and a contract from the Atlantic Innovation Fund (contract no. 2061-1004933-1). The sponsors did not play any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Publisher Copyright:
© 2018 Federation of European Biochemical Societies
ASJC Scopus Subject Areas
- Biophysics
- Structural Biology
- Biochemistry
- Molecular Biology
- Genetics
- Cell Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't