Kinetics and mechanism of penicillin aminolysis involved in penicillin allergy

Yamana, Tsukinaka; Tsuji, Akira; Miyamoto, Etsuko; Kiya, Emi

doi:10.1111/j.2042-7158.1975.tb09382.x

Cited by 18 publications

(12 citation statements)

References 10 publications

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“…The results for the FSASA analysis revealed that buried Lys residues were more prone to modification by flucloxacillin than surface ones, which was reflected in the fact that the mean accessible surface area was lower for the modified than the unmodified residues ( p =0.03, t ‐test). It has been reported that the sites of covalent modification of proteins by benzylpenicillin may be influenced by the proximity of certain other residues, particularly serine or histidine: both of these residues have been suggested as the original target for penicilloylation, followed by transesterification to a nearby lysine 19. In the case of flucloxacillin, there was no significant difference between modified and unmodified lysine residues with respect to the calculated distance between the ε‐amino nitrogen of the lysine and the imidazole ring of the nearest histidine residue, or the hydroxyl oxygen of the nearest serine residue (Table S1, calculated with PyMol v1.0, Delano Scientific).…”

Section: Resultsmentioning

confidence: 99%

“…The methods used to calculate the p K a of an amino acid within a protein are thought to be less precise for residues buried within hydrophobic pockets 18. Thus, the following values were calculated for HSA: the distance of each Lys from each Ser or His residue (PyMol v1.0, Delano Scientific, USA), as these are thought to be involved in deprotonation of Lys 19, 20; the fractional solvent‐accessible surface area (FSASA) as a measure of the accessibility of the Lys residues 21 and the position of the Lys residues with respect to the hydrophobic binding pockets (Sudlow sites I and II) 22. The same PDB file as above was used.…”

Section: Methodsmentioning

confidence: 99%

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Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Jenkins

Meng

Elliott

et al. 2009

Proteomics Clinical Apps

109

156

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Flucloxacillin is a synthetic penicillin used in the treatment of Staphylococcal infections. Adverse reactions to the drug are believed to arise through covalent modification of proteins, with tissue damage occurring secondary to an immune reaction. Serum proteins have been shown by adduct-specific antibodies to be modified by flucloxacillin, but the nature and sites of modification have not been characterised. Here, in vitro studies on HSA have shown by MS that the modification of protein lysine residues occurs in a dose-, time-and site-dependent manner. Affinity, cation exchange and reversed phase chromatography prior to MS revealed in vivo modification of HSA with flucloxacillin in tolerant patients, with up to nine modified lysine residues being detected in each patient, and with modification of Lys190 and Lys212 being detected in 8/8 patients. It was also revealed for the first time that plasma proteins could be modified with the 5-hydroxymethyl metabolite of flucloxacillin, and that essentially the same Lys residues were targeted by both the parent drug and its metabolite. This study provides a detailed characterisation of sites of chemical modification of an endogenous target and reveals candidate peptides for T-cell and antibody assays of flucloxacillin hypersensitivity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Jenkins

Meng

Elliott

et al. 2009

Proteomics Clinical Apps

109

156

View full text Add to dashboard Cite

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“…In addition, allergy skin tests for the determination of IgE antibodies to penicillins consist of the penicilloyl reagent from the aminolysis of the β‐lactam ring by polylysine or HSA carrier molecules 2. To understand further these biochemical processes, the aminolysis of β‐lactam compounds has been extensively studied experimentally 3−6. For a series of primary monoamines, it has been found that the importance of the different reaction pathways for the disappearance of the β‐lactam compounds in aqueous amine solution depends on the p K a , the concentration of the amine, and the pH.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study of Amine-Assisted Aminolysis of Penicillins − The Kinetic Role of the Carboxylate Group

2001

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The β‐lactam ring opening of 3α‐carboxypenam through a methylamine aminolysis reaction catalyzed by another methylamine molecule is studied at the B3LYP/6−31+G* level of theory. Two different neutral mechanisms have been found: a concerted one and a stepwise route through two neutral tetrahedral intermediates. In the gas‐phase the most favorable mechanism is stepwise, in which the carboxylate group of 3α‐carboxypenam participates directly in the reaction coordinate as a proton shuttle. In aqueous solution the concerted mechanism is the most favored route in which the electrostatic effect of the carboxylate group plays an important role by enhancement of the solute‐solvent interaction. The structure and molecular properties of the concerted transition state correlate well with the experimentally reported Brønsted β value and with the greater catalytic advantage of amines compared with water in the aminolysis of penicillins. These effects of the carboxylate group may be of some relevance, not only to understand the aminolysis of β‐lactam antibiotics, but also to understand their hydrolysis in aqueous or enzymatic environments.

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“…In the experimental study of the aminolysis of benzylpenicillin in aqueous solutions of a series of primary monoamines and ammonia, it has been found that the importance of the different terms contributing to the observed pseudo-first-order rate constant for the disappearance of the penicillin depends on the basicity and concentration of the amine and the pH. , Particularly interesting are the kinetic terms corresponding to the uncatalyzed and amine-catalyzed aminolysis, which are the predominant terms when weakly basic amines are employed in the biologically relevant region pH 6−8. Thus, a logarithmic plot of the kinetic constant k b for a rate dependence on [RNH 2 ] 2 against the p K a of the amines is a straight line, the slope of which gives the Brønsted β-value of 1.09.…”

Section: Introductionmentioning

confidence: 99%

NH₃-Assisted Ammonolysis of β-Lactams: A Theoretical Study

1999

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The ring opening of 2-azetidinone via a neutral NH(3)-assisted ammonolysis process is studied using different quantum chemical methods (MP2/6-31G, B3LYP/6-31G, and G2(MP2,SVP) levels of theory) as a first step toward the understanding of the aminolysis reaction of beta-lactam antibiotics. The exploration of the corresponding potential energy surfaces renders two different mechanistic routes for the ammonolysis process catalyzed by one ammonia molecule: a concerted pathway and a stepwise one through a tetrahedral intermediate. The gas-phase activation Gibbs energies (G2(MP2,SVP) electronic energies and B3LYP/6-31G thermal corrections) predict that the nonconcerted route is the more favored one, presenting a DeltaG for the ring opening of the tetrahedral intermediate of 51.9 kcal/mol with respect to the separate reactants. This gas-phase DeltaG value is 4.9 kcal/mol lower than that for the concerted process. When the MP2/6-31G SCRF electrostatic solvation Gibbs energy is taken into account, the resultant DeltaG value in solution for the stepwise rate-determining step is 55.8 kcal/mol (1.8 kcal/mol lower than the corresponding DeltaG value for the concerted route). The catalytic effect of the second ammonia molecule on the stepwise mechanism amounts to 2.4 and 0.8 kcal/mol in terms of Gibbs energies in the gas phase and in solution, respectively. The rate-determining transition state has structural characteristics in accordance with the experimental interpretation of Brønsted plots for the aminolysis reaction of benzylpenicillin in which the catalytic moiety resembles an ammonium cation. Interestingly, a comparative analysis of our theoretical results for the ammonia-assisted ammonolysis of azetidinones and those previously reported for the water-assisted hydrolysis shows that the two reactions follow opposite trends regarding the energetic and structural nature of their rate-determining transition structures. The Gibbs energy profiles reported in this work may be useful as a preliminary study to understand the aminolysis reaction of beta-lactam antibiotics.

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Kinetics and mechanism of penicillin aminolysis involved in penicillin allergy

Cited by 18 publications

References 10 publications

Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Theoretical Study of Amine-Assisted Aminolysis of Penicillins − The Kinetic Role of the Carboxylate Group

NH₃-Assisted Ammonolysis of β-Lactams: A Theoretical Study

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Kinetics and mechanism of penicillin aminolysis involved in penicillin allergy

Cited by 18 publications

References 10 publications

Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Characterisation of flucloxacillin and 5‐hydroxymethyl flucloxacillin haptenated HSA in vitro and in vivo

Theoretical Study of Amine-Assisted Aminolysis of Penicillins − The Kinetic Role of the Carboxylate Group

NH3-Assisted Ammonolysis of β-Lactams: A Theoretical Study

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NH₃-Assisted Ammonolysis of β-Lactams: A Theoretical Study