A catalytic mechanism for cysteine N-terminal nucleophile hydrolases, as revealed by free energy simulations

The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydro...

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Bibliographic Details
Published in:PloS one 2012-02, Vol.7 (2), p.e32397-e32397
Main Authors: Lodola, Alessio, Branduardi, Davide, De Vivo, Marco, Capoferri, Luigi, Mor, Marco, Piomelli, Daniele, Cavalli, Andrea
Format: Article
Language:English
Subjects:
Amidohydrolases - chemistry
Amidohydrolases - genetics
Amidohydrolases - metabolism
Biology
Cancer
Catalysis
Chemical bonds
Chemical reactions
Chemistry
Computational Biology - methods
Computer applications
Computer simulation
Cysteine
Cystine
Deoxycholic acid
Enzymes
Fatty acids
Free energy
Hydrolase
Hydrolases
Hydrolysis
Hypotheses
Molecular Dynamics Simulation
Mutants
Mutation
Pain
Pharmaceuticals
Protein Structure, Secondary
Quantum mechanics
Reaction mechanisms
Sulfur
Thiols
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Summary:The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, the catalytic reactions of cysteine Ntn-hydrolases have never been investigated from a mechanistic point of view. In the present study, we used free energy simulations in the quantum mechanics/molecular mechanics framework to determine the reaction mechanism of amide hydrolysis catalyzed by the prototypical cysteine Ntn-hydrolase, conjugated bile acid hydrolase (CBAH). The computational analyses, which were confirmed in water and using different CBAH mutants, revealed the existence of a chair-like transition state, which might be one of the specific features of the catalytic cycle of Ntn-hydrolases. Our results offer new insights on Ntn-mediated hydrolysis and suggest possible strategies for the creation of therapeutically useful inhibitors.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0032397