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Phosphoryl transfer by a concerted reaction mechanism in UMP/CMP-kinase

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Hutter,  Michael C.
Max Planck Research Group of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Helms,  Volkhard
Max Planck Research Group of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Hutter, M. C., & Helms, V. (2000). Phosphoryl transfer by a concerted reaction mechanism in UMP/CMP-kinase. Protein Science, 9(11), 2225-2231. doi:10.1110/ps.9.11.2225.


Cite as: http://hdl.handle.net/21.11116/0000-0007-D488-0
Abstract
The reaction mechanism of phosphoryl transfer catalyzed by UMP/CMP-kinase from Dictyostelium discoideum was investigated by semiempirical AM1 molecular orbital computations of an active site model system derived from crystal structures that contain a transition state analog or a bisubstrate inhibitor. The computational results suggest that the nucleoside monophosphate must be protonated for the forward reaction while it is unprotonated in the presence of aluminium fluoride, a popular transition state analog for phosphoryl transfer reactions. Furthermore, a compactification of the active site model system during the reaction and for the corresponding complex containing AlF3 was observed. For the active site residues that are part of the LID domain, conformational flexibility during the reaction proved to be crucial. On the basis of the calculations, a concerted phosphoryl transfer mechanism is suggested that involves the synchronous shift of a proton from the monophosphate to the transferred PO3-group. The proposed mechanism is thus analogous to the phosphoryl transfer mechanism in cAMP-dependent protein kinase that phosphorylates the hydroxyl groups of serine residues.