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Inhibition of O-acetylserine sulfhydrylase by fluoroalanine derivatives.

Authors :
Franko N
Grammatoglou K
Campanini B
Costantino G
Jirgensons A
Mozzarelli A
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.

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