Galactokinase promiscuity: A question of flexibility?

Megan McAuley, Helena Kristiansson, Meilan Huang, Angel L. Pey, David J. Timson

Research output: Contribution to journalArticle

Abstract

Galactokinase catalyses the first committed step of the Leloir pathway, i.e. the ATP-dependent phosphorylation of α-d-galactose at C1-OH. Reduced galactokinase activity results in the inherited metabolic disease type II galactosaemia. However, inhibition of galactokinase is considered a viable approach to treating more severe forms of galactosaemia (types I and III). Considerable progress has been made in the identification of high affinity, selective inhibitors. Although the structure of galactokinase from a variety of species is known, its catalytic mechanism remains uncertain. Although the bulk of evidence suggests that the reaction proceeds via an active site base mechanism, some experimental and theoretical studies contradict this. The enzyme has potential as a biocatalyst in the production of sugar 1-phosphates. This potential is limited by its high specificity. A variety of approaches have been taken to identify galactokinase variants which are more promiscuous. These have broadened galactokinase's specificity to include a wide range of d- and l-sugars. Initial studies suggest that some of these alterations result in increased flexibility at the active site. It is suggested that modulation of protein flexibility is at least as important as structural modifications in determining the success or failure of enzyme engineering.

Original languageEnglish
Pages (from-to)116-122
Number of pages7
JournalBiochemical Society Transactions
Volume44
DOIs
Publication statusPublished - 9 Feb 2016

Bibliographical note

This is not the final Version of Record. The final Version of Record can be found at http://www.biochemsoctrans.org/content/44/1/116

Keywords

  • Enzyme engineering
  • Enzyme mechanism
  • Galactosaemia
  • Galactose
  • GHMP kinase
  • Specificity

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