Phosphoryl Transfer Reactions

Abstract

Phosphoryl transfer is the name given to the chemical process of the transfer of the phosphoryl group (PO3) from a phosphate ester or anhydride to a nucleophile. Nucleophilic attack by water on a phosphate monoester gives the hydrolysis product inorganic phosphate. This net dephosphorylation reaction is the process catalysed by phosphatases. Although the reaction is thermodynamically favourable, it has a very high kinetic barrier, making the uncatalysed hydrolysis of phosphate esters extremely slow. The opposite process, the formation of phosphate esters, is termed phosphorylation and is accomplished in biological systems by kinases. The balance between phosphatase and kinase activities in biology serves to regulate the phosphorylation level of many enzymes and other proteins in the cell, forming an important regulatory mechanism that is found throughout the biological world.

Key Concepts

  • The postā€translational phosphorylation levels of proteins are regulated by the complimentary actions of phosphatases and kinases.
  • The uncatalysed hydrolysis of phosphate esters has a very high kinetic barrier, making phosphatases among the most efficient enzymes known.
  • The various families of phosphatases use different catalytic machinery and mechanisms to carry out phosphate ester hydrolysis.

Keywords: phosphate ester; phosphatase; kinase; phosphorylation; signal transduction

Figure 1. The hydrolysis of a phosphate ester, consisting of the transfer of a phosphoryl group from the ester to water. In biological systems, the R group may be the nucleophilic side‐chain of an amino acid or a small molecule such as glucose.
Figure 2. Some of the components of the regulation processes governing glycogen metabolism. For a fuller picture of the regulation of this process, see Cohen ().
Figure 3. Mechanistic possibilities for the chemical step of phosphoryl transfer from a phosphate ester to a nucleophile (Nu), which is water in this example. In a dissociative mechanism, the ester group (the leaving group) departs first and the nucleophile does not participate until the second step. In an associative mechanism, the phosphoryl transfer is an addition–elimination process, in which the nucleophile adds in the first step and the leaving group departs in a subsequent step. In a concerted mechanism, the nucleophile adds and the leaving group departs in the same step.
Figure 4. The overall reaction catalysed by kinases, showing the α‐, β‐, and γ‐nomenclature for the phosphoryl groups of nucleoside triphosphates. For protein kinases, the nucleophile (Nu) is the side‐chain of threonine, serine, tyrosine or histidine.
Figure 5. A representation of the residues at the active site of cAMP‐dependent protein kinase that mechanistic studies indicate are involved in interactions with the substrate ATP and/or in the catalytic reaction.
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References

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Further Reading

(2013) Biochimica et Biphysica Acta Proteins and Proteomics 1834: 413–478. [A special section of this issue reports recent developments in the chemistry and mechanism of phosphatases, diesterases, and triesterases.].

(2001) Chemical Reviews 101 (8). [This is a special issue devoted to the topics of protein phosphorylation and signalling, and contains a number of relevant articles.].

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Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease, Nature reviews. Molecular Cell Biology 7: 833–846.

Westheimer FH (1987) Why nature chose phosphates. Science 235: 1173–1178.

Zhang ZY (2002) Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annual Reviews in Pharmacology and Toxicology 42: 209–234.

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How to Cite close
Hengge, Alvan C(Jan 2015) Phosphoryl Transfer Reactions. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000608.pub2]