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Inhibition of O-acetylserine sulfhydrylase by fluoroalanine derivatives.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2018 Dec; Vol. 33 (1), pp. 1343-1351. - Publication Year :
- 2018
-
Abstract
- O-acetylserine sulfhydrylase (OASS) is the pyridoxal 5'-phosphate dependent enzyme that catalyses the formation of L-cysteine in bacteria and plants. Its inactivation is pursued as a strategy for the identification of novel antibiotics that, targeting dispensable proteins, holds a great promise for circumventing resistance development. In the present study, we have investigated the reactivity of Salmonella enterica serovar Typhimurium OASS-A and OASS-B isozymes with fluoroalanine derivatives. Monofluoroalanine reacts with OASS-A and OASS-B forming either a stable or a metastable α-aminoacrylate Schiff's base, respectively, as proved by spectral changes. This finding indicates that monofluoroalanine is a substrate analogue, as previously found for other beta-halogenalanine derivatives. Trifluoroalanine caused different and time-dependent absorbance and fluorescence spectral changes for the two isozymes and is associated with irreversible inhibition. The time course of enzyme inactivation was found to be characterised by a biphasic behaviour. Partially distinct inactivation mechanisms for OASS-A and OASS-B are proposed.
- Subjects :
- Alanine chemical synthesis
Alanine chemistry
Alanine pharmacology
Cysteine Synthase metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Molecular Structure
Salmonella enterica enzymology
Structure-Activity Relationship
Alanine analogs & derivatives
Cysteine Synthase antagonists & inhibitors
Enzyme Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 33
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30251899
- Full Text :
- https://doi.org/10.1080/14756366.2018.1504040