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Quinone Methide‐Based Organophosphate Hydrolases Inhibitors: Trans Proximity Labelers versus Cis Labeling Activity‐Based Probes
- Source :
- ChemBioChem. 22:894-903
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Quinone methide (QM) chemistry is widely applied including in enzyme inhibitors. Typically, enzyme-mediated bond breaking releases a phenol product that rearranges into an electrophilic QM that in turn covalently modifies protein side chains. However, the factors that govern the reactivity of QM-based inhibitors and their mode of inhibition have not been systematically explored. Foremost, enzyme inactivation might occur in cis, whereby a QM molecule inactivates the very same enzyme molecule that released it, or by trans if the released QMs diffuse away and inactivate other enzyme molecules. We examined QM-based inhibitors for enzymes exhibiting phosphoester hydrolase activity. We tested different phenolic substituents and benzylic leaving groups, thereby modulating the rates of enzymatic hydrolysis, phenolate-to-QM rearrangement, and the electrophilicity of the resulting QM. By developing assays that distinguish between cis and trans inhibition, we have identified certain combinations of leaving groups and phenyl substituents that lead to inhibition in the cis mode, while other combinations gave trans inhibition. Our results suggest that cis-acting QM-based substrates could be used as activity-based probes to identify various phospho- and phosphono-ester hydrolases, and potentially other hydrolases.
- Subjects :
- chemistry.chemical_classification
010405 organic chemistry
Stereochemistry
Hydrolysis
Organic Chemistry
010402 general chemistry
01 natural sciences
Biochemistry
Quinone methide
Organophosphates
Phosphoric Monoester Hydrolases
0104 chemical sciences
Turn (biochemistry)
chemistry.chemical_compound
Enzyme
chemistry
Covalent bond
Enzymatic hydrolysis
Phosphodiester bond
Electrophile
Molecular Medicine
Enzyme Inhibitors
Indolequinones
Molecular Biology
Cis–trans isomerism
Subjects
Details
- ISSN :
- 14397633 and 14394227
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- ChemBioChem
- Accession number :
- edsair.doi.dedup.....0c1ffe650ecee4d3b4689c5f51a0d800