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Nature Chemistry: The Role of Conformational Movements for Enzyme Function

13 April 2012

Nature Chemistry

The role of protein motions in enzyme catalysis is a key issue in modern enzymology. One of the most studied enzymes in this area, both internationally and here at Cardiff University in the group of Professor Rudolf K Allemann, is the dihydrofolate reductase from E. coli (EcDHFR), an enzyme that catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate. Previously, a ‘dynamic knockout’ mutant of EcDHFR with a reduced reaction rate was reported by groups at the Scripps Research Institute and Penn State University. It was suggested that the decreased activity of the ‘dynamic knockout’ was a consequence of a loss of protein dynamics, directly associated with hydride transfer . Dr Joel Loveridge, Enas Behiry and Jiannan Guo in the Allemann group have now provided experimental data that shows that the chemistry of the reaction is essentially the same in the ‘dynamic knockout’ as in the wild-type enzyme. The decrease in enzyme activity is therefore not a direct result of an impairment of protein dynamics. Instead, the conformational state of the enzyme immediately prior to hydride transfer, which determines the electrostatic environment of the active site, affects the rate constant of the reaction. These results have wide implications for our understanding of enzymatic catalysis and our ability to control biologically importnat molecules in vivo with applications inter alia in research, medicine, agrochemistry and green energy. The work has recently been published in Nature Chemistry (http://www.nature.com/nchem/journal/v4/n4/full/nchem.1296.html).