Theoretical site-directed mutagenesis. The Asp168Ala mutant of L-Lactate Dehydrogenase
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Other documents of the author: Moliner, Vicent; Ferrer Castillo, Silvia; Silla, Estanislao; Tuñón, Iñaki; Williams, Ian H.
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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Title
Theoretical site-directed mutagenesis. The Asp168Ala mutant of L-Lactate DehydrogenaseAuthor (s)
Date
2008Publisher
Royal Society (Gran Bretanya)ISSN
17425689Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/acceptedVersionSubject
Abstract
The reduction of pyruvate to lactate catalyzed by the L-Lactate
dehydrogenase has been studied in this paper by means of hybrid Quantum Mechanical
/ Molecular Mechanical simulations. A very flexible molecular model ... [+]
The reduction of pyruvate to lactate catalyzed by the L-Lactate
dehydrogenase has been studied in this paper by means of hybrid Quantum Mechanical
/ Molecular Mechanical simulations. A very flexible molecular model consisting on the
full tetramer of the enzyme, together with the cofactor NADH, the substrate and solvent
water molecules has allowed to theoretically mimic site directed mutagenesis studies,
most of them previously experimentally performed. The potential energy surfaces
obtained for every single mutation, compared with the one corresponding to the native
enzyme, have been used to trace the possible reaction pathways and to locate and
characterize the structures corresponding to the stationary points. The analysis of the
results has been a very powerful tool to conclude about the role of key residues on the
vacuole formed in the active site of the enzyme. Our results are in very good agreement
with the previous conclusions derived from site directed mutagenesis. This strategy can
be extrapolated to other enzyme systems thus opening the door of a very promising
methodology that, in combination with the appropriate experimental technique, will
enable us to describe enzyme catalysis phenomenon and the particular role of the
residues that form the protein. This knowledge placed us in a privileged position to
modify the activity of enzymes and to propose efficient inhibitors [-]
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