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À propos de : Different Transition-State Structures for the Reactions ofβ-Lactams and Analogous β-Sultams with Serineβ-Lactamases        

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  • Different Transition-State Structures for the Reactions ofβ-Lactams and Analogous β-Sultams with Serineβ-Lactamases
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  • β-Sultams are the sulfonyl analogues of β-lactams, and N-acyl β-sultams are novel inactivatorsof the class C β-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue toform a sulfonate ester which subsequently undergoes C−O bond fission and formation of a dehydroalanineresidue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. Theanalogous N-acyl β-lactams are substrates for β-lactamase and undergo enzyme-catalyzed hydrolysispresumably by the normal acylation−deacylation process. The rates of acylation of the enzyme by theβ-lactams, measured by the second-order rate constant for hydrolysis, kcat/Km, and those of sulfonylationby the β-sultams, measured by the second-order rate constant for inactivation, ki, both show a similar pHdependence to that exhibited by the β-lactamase-catalyzed hydrolysis of β-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl β-lactams increase the rate of alkalinehydrolysis and give a Bronsted βlg of −0.55, indicative of a late transition state for rate-limiting formationof the tetrahedral intermediate. Interestingly, the corresponding Bronsted βlg for the β-lactamase-catalyzedhydrolysis of the same substrates is −0.06, indicative of an earlier transition state for the enzyme-catalyzedreaction. By contrast, although the Bronsted βlg for the alkaline hydrolysis of N-aroyl β-sultams is −0.73,similar to that for the β-lactams, that for the sulfonylation of β-lactamase by these compounds is −1.46,compatible with significant amide anion expulsion/S−N fission in the transition state. In this case, the enzymereaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the β-sultam.
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