873073-30-4Relevant articles and documents
Different transition-state structures for the reactions of β-lactams and analogous β-sultams with serine β-lactamases
Tsang, Wing Y.,Ahmed, Naveed,Hinchliffe, Paul S.,Wood, J. Matthew,Harding, Lindsay P.,Laws, Andrew P.,Page, Michael I.
, p. 17556 - 17564 (2005)
β-Sultams are the sulfonyl analogues of β-lactams, and N-acyl β-sultams are novel inactivators of the class C β-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl β-lactams are substrates for β-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the β-lactams, measured by the second-order rate constant for hydrolysis, kcat/Km, and those of sulfonylation by the β-sultams, measured by the second-order rate constant for inactivation, ki, both show a similar pH dependence 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 alkaline hydrolysis and give a Bronsted βIg of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted βIg for the β-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted βIg 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 enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the β-sultam.
Competitive endo- and exo-cyclic C-N fission in the hydrolysis of N-aroyl β-lactams
Tsang, Wing Y.,Ahmed, Naveed,Hemming, Karl,Page, Michael I.
, p. 1432 - 1439 (2007/10/03)
The balance between endo- and exo-cyclic C-N fission in the hydrolysis of N-aroyl β-lactams shows that the difference in reactivity between strained β-lactams and their acyclic analogues is minimal. Attack of hydroxide ion occurs preferentially at the exocyclic acyl centre rather than that of the β-lactam during the hydrolysis of N-p-nitrobenzoyl β-lactam. In general, both endo- and exo-cyclic C-N bond fission occurs in the alkaline hydrolysis of N-aroyl β-lactams, the ratio of which varies with the aryl substituent. Hence, the Bronsted β-values differ for the two processes: -0.55 for the ring-opening reaction and -1.54 for the exocyclic C-N bond fission reaction. For the pH-independent and acid-catalysed hydrolysis of N-benzoyl β-lactam, less than 3% of products are derived from exocyclic C-N bond fission.
