Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase
Alessio Lodola 1, Marco Mor 1, Jolanta Zurek 2, Giorgio Tarzia 3, Daniele Piomelli 4, Jeremy Noel Harvey 2 and Adrian John Mulholland 2*
1 Università di Parma
2 University of Bristol
3 Università di Urbino
4 University of California
* To whom correspondence should be addressed. E-mail: adrian.mulholland{at}bristol.ac.uk.
Submitted on September 29, 2006
Revised on October 6, 2006
Accepted on 2 November 2006
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Abstract |
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QM/MM and molecular dynamics simulations of fatty acid amide hydrolase (FAAH) show that reaction (amide hydrolysis) occurs via a distinct, high energy conformation. This unusual finding has important implications for FAAH, a key enzyme in the endocannabinoid system. These results demonstrate the importance of structural fluctuations, and the need to include them in the modelling of enzyme reactions. They also show that approaches based simply on studying enzyme-substrate complexes can be misleading for understanding biochemical reactivity.
Key Words:
Curtin-Hammett principle, Enzyme Catalysis, FAAH, Molecular Dynamics, QM/MM, Structural Fluctuations
