Abstract
Cysteine is a building block for many biomolecules that are crucial for living organisms. O-Acetylserine sulfhydrylase (OASS), present in bacteria and plants but absent in mammals, catalyzes the last step of cysteine biosynthesis. This enzyme has been deeply investigated because, beside the biosynthesis of cysteine, it exerts a series of “moonlighting” activities in bacteria. We have previously reported a series of molecules capable of inhibiting Salmonella typhimurium (S. typhymurium) OASS isoforms at nanomolar concentrations, using a combination of computational and spectroscopic approaches. The cyclopropane-1,2-dicarboxylic acids presented herein provide further insights into the binding mode of small molecules to OASS enzymes. Saturation transfer difference NMR (STD-NMR) was used to characterize the molecule/enzyme interactions for both OASS-A and B. Most of the compounds induce a several fold increase in fluorescence emission of the pyridoxal 5′-phosphate (PLP) coenzyme upon binding to either OASS-A or OASS-B, making these compounds excellent tools for the development of competition-binding experiments.
| Original language | English |
|---|---|
| Pages (from-to) | 78-87 |
| Number of pages | 10 |
| Journal | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Volume | 31 |
| DOIs | |
| Publication status | Published - Nov 4 2016 |
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Keywords
- cyclopropane-1,2-dicarboxylic acids
- cysteine biosynthesis
- drug resistance
- O-Acetylserine sulfhydrylase
- saturation transfer difference-NMR
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
Cite this
Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation of O-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR. / Annunziato, Giannamaria; Pieroni, Marco; Benoni, Roberto; Campanini, Barbara; Pertinhez, Thelma A.; Pecchini, Chiara; Bruno, Agostino; Magalhães, Joana; Bettati, Stefano; Franko, Nina; Mozzarelli, Andrea; Costantino, Gabriele.
In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 31, 04.11.2016, p. 78-87.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cyclopropane-1,2-dicarboxylic acids as new tools for the biophysical investigation of O-acetylserine sulfhydrylases by fluorimetric methods and saturation transfer difference (STD) NMR
AU - Annunziato, Giannamaria
AU - Pieroni, Marco
AU - Benoni, Roberto
AU - Campanini, Barbara
AU - Pertinhez, Thelma A.
AU - Pecchini, Chiara
AU - Bruno, Agostino
AU - Magalhães, Joana
AU - Bettati, Stefano
AU - Franko, Nina
AU - Mozzarelli, Andrea
AU - Costantino, Gabriele
PY - 2016/11/4
Y1 - 2016/11/4
N2 - Cysteine is a building block for many biomolecules that are crucial for living organisms. O-Acetylserine sulfhydrylase (OASS), present in bacteria and plants but absent in mammals, catalyzes the last step of cysteine biosynthesis. This enzyme has been deeply investigated because, beside the biosynthesis of cysteine, it exerts a series of “moonlighting” activities in bacteria. We have previously reported a series of molecules capable of inhibiting Salmonella typhimurium (S. typhymurium) OASS isoforms at nanomolar concentrations, using a combination of computational and spectroscopic approaches. The cyclopropane-1,2-dicarboxylic acids presented herein provide further insights into the binding mode of small molecules to OASS enzymes. Saturation transfer difference NMR (STD-NMR) was used to characterize the molecule/enzyme interactions for both OASS-A and B. Most of the compounds induce a several fold increase in fluorescence emission of the pyridoxal 5′-phosphate (PLP) coenzyme upon binding to either OASS-A or OASS-B, making these compounds excellent tools for the development of competition-binding experiments.
AB - Cysteine is a building block for many biomolecules that are crucial for living organisms. O-Acetylserine sulfhydrylase (OASS), present in bacteria and plants but absent in mammals, catalyzes the last step of cysteine biosynthesis. This enzyme has been deeply investigated because, beside the biosynthesis of cysteine, it exerts a series of “moonlighting” activities in bacteria. We have previously reported a series of molecules capable of inhibiting Salmonella typhimurium (S. typhymurium) OASS isoforms at nanomolar concentrations, using a combination of computational and spectroscopic approaches. The cyclopropane-1,2-dicarboxylic acids presented herein provide further insights into the binding mode of small molecules to OASS enzymes. Saturation transfer difference NMR (STD-NMR) was used to characterize the molecule/enzyme interactions for both OASS-A and B. Most of the compounds induce a several fold increase in fluorescence emission of the pyridoxal 5′-phosphate (PLP) coenzyme upon binding to either OASS-A or OASS-B, making these compounds excellent tools for the development of competition-binding experiments.
KW - cyclopropane-1,2-dicarboxylic acids
KW - cysteine biosynthesis
KW - drug resistance
KW - O-Acetylserine sulfhydrylase
KW - saturation transfer difference-NMR
UR - http://www.scopus.com/inward/record.url?scp=85006325057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006325057&partnerID=8YFLogxK
U2 - 10.1080/14756366.2016.1218486
DO - 10.1080/14756366.2016.1218486
M3 - Article
C2 - 27578398
AN - SCOPUS:85006325057
VL - 31
SP - 78
EP - 87
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
ER -