Water-Assisted Alkaline Hydrolysis of Monobactams: A Theoretical Study

Díaz, Natalia; Suárez, Dimas; Sordo, T. L.; Tuñón, Iñaki; Silla, Estanislao

doi:10.1002/1521-3765(20020215)8:4<859::aid-chem859>3.0.co;2-i

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…7 This activation is clearly revealed by the elongation of the β‐lactam CN bond with respect to the isolated penam (1.379 Å): 1.487 ( 3 S ), 1.422 ( 6 S ), and 1.421 Å ( 2 S ). These values are similar to those found in some tetrahedral intermediates for the alkaline hydrolysis of 2‐azetidinone (1.573 Å),31 N ‐methyl‐2‐azetidinone (1.519 Å),32 3‐formylamino‐2‐azetidinone (1.521 Å),31 and 3‐formylamino‐2‐azetidine‐1‐sulfonate ion, (1.545 Å)31 and particularly for the neutral hydrolysis of N ‐methyl‐2‐azetidinone (1.449 Å) 32. This seems to indicate that the formation of these kinds of complexes between Cu II and β‐lactam antibiotics could belong to the reaction coordinate for degradation of these drugs in the presence of this metal ion.…”

Section: Resultssupporting

confidence: 88%

A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond

et al. 2005

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The interaction of CuII with 6-formylamino-3alpha-carboxypenam and 6-acetylamino-3alpha-carboxypenam was investigated by means of DFT calculations with the UB3LYP functional. Nine different modes of complexation between CuII and 6-formylamino-3alpha-carboxypenam were located. When two water molecules directly bonded to CuII are included in the calculations on 6-acetylamino-3alpha-carboxypenam as penicillin model, only six CuII(H2O)2-6-acetylamino-3alpha-carboxypenam complexes (1S-6S) are found. In solution the four most stable complexes obtained from our calculations, 6S, 1S, 2S, and 3S, exhibit CuII in square-planar coordination with at least one bond to the carboxylate group, in agreement with experimental evidence. Complexes 6S, 1S, and 3S were previously suggested by available experimental evidence. In three of the most stable complexes (6S, 2S, and 3S) the beta-lactam C-N bond is remarkably activated and displays C-N bond lengths similar to those found in some tetrahedral intermediates located for the hydrolysis of 2-azetidinones. This suggests that these kinds of complexes belong to the reaction coordinate for the degradation of beta-lactam antibiotics in the presence of CuII.

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Section: Resultssupporting

confidence: 88%

A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond

et al. 2005

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“…The rate-limiting step is the formation of the tetrahedral intermediate, whereas the barrier for elimination is very small. These results are consistent with previous theoretical studies of ␤-lactam hydrolysis (35,36).…”

Section: Resultsmentioning

confidence: 99%

Catalytic Mechanism of Class B2 Metallo-β-lactamase

Xie

Guo

2006

Journal of Biological Chemistry

105

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The initial nucleophilic substitution step of biapenem hydrolysis catalyzed by a subclass B2 metallo-␤-lactamase (CphA from Aeromonas hydrophila) is investigated using hybrid quantum mechanical/molecular mechanical methods and density functional theory. We focused on a recently proposed catalytic mechanism that involves a non-metal-binding water nucleophile in the active site of the monozinc CphA. Both theoretical models identified a single transition state featuring nearly concomitant nucleophilic addition and elimination steps, and the activation free energy from the potential of mean force calculations was estimated to be ϳ14 kcal/ mol. The theoretical results also identified the general base for activating the water nucleophile to be the metal-binding Asp-120 rather than His-118, as suggested earlier. The protonation of Asp-120 leads to cleavage of the O ␦2 -Zn coordination bond, whereas the negatively charged nitrogen leaving group resulting from the ring opening replaces Asp-120 as the fourth ligand of the sole zinc ion. The electrophilic catalysis by the metal ion provides sufficient stabilization for the leaving group to avoid a tetrahedral intermediate. The theoretical studies provided detailed insights into the catalytic strategy of this unique metallo-␤-lactamase.The excessive use and abuse of ␤-lactam antibiotics have accelerated the spread of drug-resistant bacterial strains. The unprecedented level of antibiotic resistance threatens to destroy their efficacy in treating infectious diseases, posing a grand challenge to public health (1). The primary defense strategy adopted by bacteria is to deactivate the antibiotics by hydrolytic cleavage of the ␤-lactam ring, catalyzed by ␤-lactamases (2). These enzymes can be divided into four classes (3). Enzymes in classes A, C, and D utilize an active site serine in the covalent catalysis of the ␤-lactam hydrolysis, whereas class B consists of metalloenzymes with one or two zinc cofactors. Although the catalytic mechanism of the serine-based enzymes is relatively well established (2), our understanding of class B ␤-lactamases is less developed (4).Metallo-␤-lactamases often have very broad substrate spectra (5) stemming apparently from the metal-dependent catalytic mechanism. Despite much effort, no clinically effective inhibitor has been found. On the other hand, increasing evidence in recent years has pointed to rapid proliferation of these metalloenzymes in pathogenic microorganisms (6). Hence, these enzymes represent a potentially more potent threat to the existing arsenal of ␤-lactam antibiotics than other classes of ␤-lactamases (5, 6).Class B ␤-lactamases can be further separated into three subclasses. Despite considerable sequence diversity (4), their catalytic scaffolds are relatively conserved. All class B ␤-lactamases have two potential metal binding sites (7-11). Protein ligands in the so-called Zn1 site include three His residues in the B1 and B3 subclasses, but a His residue is replaced by Asn in B2 subclass ␤-lactamases. The Zn2 site has an Asp...

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“…To explore the conformational behaviors in solution qualitatively, quantum chemical computations were carried out on gas phase optimized geometries using the polarized continuum model (PCM) within the framework of SCRF theory [17], which has been quite successful in describing the solvent effects on the reaction [18,19]. The standard dielectric constant of water implemented in the Gaussian program was employed.…”

Section: Computational Detailsmentioning

confidence: 99%

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

Feng

et al. 2005

Struct Chem

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The alcoholysis mechanisms of N-benzyl 3-oxo-β-sultam are investigated at B3LYP/6-31G * level. Different possible mechanistic pathways of the reaction are proposed. The results show that the cleavage of S N bond producing P1 has a little lower energy barrier than does C N bond producing P2. The inclusion of solvent effects by a polarizable continuum model (PCM) does not change the conclusions based on the gas-phase study.

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Water-Assisted Alkaline Hydrolysis of Monobactams: A Theoretical Study

Cited by 12 publications

References 38 publications

A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond

A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond

Catalytic Mechanism of Class B2 Metallo-β-lactamase

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

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Water-Assisted Alkaline Hydrolysis of Monobactams: A Theoretical Study

Cited by 12 publications

References 38 publications

A Theoretical Analysis of the Coordination Modes of CuIIwith Penicillins: Activation of the β‐Lactam CN Bond

A Theoretical Analysis of the Coordination Modes of CuIIwith Penicillins: Activation of the β‐Lactam CN Bond

Catalytic Mechanism of Class B2 Metallo-β-lactamase

Theoretical Study for Alcoholysis of N-Benzyl 3-Oxo-?-Sultam

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A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond

A Theoretical Analysis of the Coordination Modes of Cu^IIwith Penicillins: Activation of the β‐Lactam CN Bond