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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2006-3-27
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pubmed:abstractText |
The initial nucleophilic substitution step of biapenem hydrolysis catalyzed by a subclass B2 metallo-beta-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 approximately 14 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(delta2)-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-beta-lactamase.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
31
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8740-7
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pubmed:dateRevised |
2007-8-13
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pubmed:meshHeading |
pubmed-meshheading:16423823-Aeromonas hydrophila,
pubmed-meshheading:16423823-Aspartic Acid,
pubmed-meshheading:16423823-Bacterial Proteins,
pubmed-meshheading:16423823-Binding Sites,
pubmed-meshheading:16423823-Carbapenems,
pubmed-meshheading:16423823-Catalysis,
pubmed-meshheading:16423823-Hydrolysis,
pubmed-meshheading:16423823-Ligands,
pubmed-meshheading:16423823-Models, Chemical,
pubmed-meshheading:16423823-Models, Molecular,
pubmed-meshheading:16423823-Models, Theoretical,
pubmed-meshheading:16423823-Protein Binding,
pubmed-meshheading:16423823-Protein Conformation,
pubmed-meshheading:16423823-Protons,
pubmed-meshheading:16423823-Quantum Theory,
pubmed-meshheading:16423823-Thermodynamics,
pubmed-meshheading:16423823-Thienamycins,
pubmed-meshheading:16423823-Water,
pubmed-meshheading:16423823-Zinc,
pubmed-meshheading:16423823-beta-Lactamases
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pubmed:year |
2006
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pubmed:articleTitle |
Catalytic mechanism of class B2 metallo-beta-lactamase.
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pubmed:affiliation |
Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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