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Catalytic scaffolds for phosphoryl group transfer.

ABSTRACT: A single genome encodes a large number of phosphoryl hydrolases for the purposes of phosphate recycling, primary and secondary metabolism, signal transduction and regulation, and protection from xenobiotics. Phosphate monoester hydrolysis faces a high kinetic barrier, yet there are multiple solutions to the problem both in terms of catalytic mechanisms and three-dimensional structure of the hydrolases. Recent structural and mechanistic findings highlight the trigonal-bipyramidal nature of the transition state for enzyme promoted phosphate monoester hydrolysis and the evolution and role of inserted loops/domains in governing substrate specificity and promiscuity. Important questions remain as to how electrostatics modulate water networks and critical proton-transfer events. How substrate targeting and catalysis is achieved by the independently evolved catalytic platforms is compared and contrasted in this article.

SUBMITTER: Allen KN

PROVIDER: S-EPMC5154885 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Catalytic scaffolds for phosphoryl group transfer.

Allen Karen N KN Dunaway-Mariano Debra D

Current opinion in structural biology 20160813

A single genome encodes a large number of phosphoryl hydrolases for the purposes of phosphate recycling, primary and secondary metabolism, signal transduction and regulation, and protection from xenobiotics. Phosphate monoester hydrolysis faces a high kinetic barrier, yet there are multiple solutions to the problem both in terms of catalytic mechanisms and three-dimensional structure of the hydrolases. Recent structural and mechanistic findings highlight the trigonal-bipyramidal nature of the tr ...[more]

PMID: 27526404

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Project description:BACKGROUND: The kinome is made up of a large number of functionally diverse enzymes, with the classification indicating very little about the extent of the conserved kinetic mechanisms associated with phosphoryl transfer. It has been demonstrated that C8-H of ATP plays a critical role in the activity of a range of kinase and synthetase enzymes. RESULTS: A number of conserved mechanisms within the prescribed kinase fold families have been identified directly utilizing the C8-H of ATP in the initiation of phosphoryl transfer. These mechanisms are based on structurally conserved amino acid residues that are within hydrogen bonding distance of a co-crystallized nucleotide. On the basis of these conserved mechanisms, the role of the nucleotide C8-H in initiating the formation of a pentavalent intermediate between the ?-phosphate of the ATP and the substrate nucleophile is defined. All reactions can be clustered into two mechanisms by which the C8-H is induced to be labile via the coordination of a backbone carbonyl to C6-NH2 of the adenyl moiety, namely a "push" mechanism, and a "pull" mechanism, based on the protonation of N7. Associated with the "push" mechanism and "pull" mechanisms are a series of proton transfer cascades, initiated from C8-H, via the tri-phosphate backbone, culminating in the formation of the pentavalent transition state between the ?-phosphate of the ATP and the substrate nucleophile. CONCLUSIONS: The "push" mechanism and a "pull" mechanism are responsible for inducing the C8-H of adenyl moiety to become more labile. These mechanisms and the associated proton transfer cascades achieve the proton transfer via different family-specific conserved sets of amino acids. Each of these mechanisms would allow for the regulation of the rate of formation of the pentavalent intermediate between the ATP and the substrate nucleophile. Phosphoryl transfer within kinases is therefore a specific event mediated and regulated via the coordination of the adenyl moiety of ATP and the C8-H of the adenyl moiety.

Dataset Information

Catalytic scaffolds for phosphoryl group transfer.

Publications

Catalytic scaffolds for phosphoryl group transfer.

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