Galactokinase: structure, function and role in type II galactosemia

  title={Galactokinase: structure, function and role in type II galactosemia},
  author={Hazel M. Holden and James B. Thoden and David J. Timson and Richard J. Reece},
  journal={Cellular and Molecular Life Sciences CMLS},
Abstract.The conversion of beta-D-galactose to glucose 1-phosphate is accomplished by the action of four enzymes that constitute the Leloir pathway. Galactokinase catalyzes the second step in this pathway, namely the conversion of alpha-D-galactose to galactose 1-phosphate. The enzyme has attracted significant research attention because of its important metabolic role, the fact that defects in the human enzyme can result in the diseased state referred to as galactosemia, and most recently for… 

Molecular Structure of Human Galactokinase

The three-dimensional architecture of human galactokinase with bound α-d-galactose and Mg-AMPPNP is reported to provide molecular insight into the active site geometry of the enzyme and provides a structural framework to more fully understand the consequences of the those mutations known to give rise to Type II galactosemia.

The Molecular Architecture of Human N-Acetylgalactosamine Kinase*

From this investigation, the geometry of the GalNAc kinase active site before and after catalysis has been revealed, and the determinants of substrate specificity have been defined on a molecular level.

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The Molecular Architecture of Galactose Mutarotase/UDP-Galactose 4-Epimerase from Saccharomyces cerevisiae*

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Galactose metabolism in yeast-structure and regulation of the leloir pathway enzymes and the genes encoding them.

Galactose Metabolism in Saccharomyces cerevisiae

Galactose metabolism in S. cerevisiae is of interest because it can be exploited both in the laboratory and industrially (increasing flux through the Leloir pathway in order to make more efficient use of feedstocks with high galactose content) and how these might be exploited commercially.

Galactokinase promiscuity: a question of flexibility?

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.

Analysis of UDP-galactose 4′-epimerase mutations associated with the intermediate form of type III galactosaemia

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Molecular Structure of Galactokinase*

The structure of galactokinase described here serves as a model for understanding the functional consequences of point mutations known to result in Type II galactosemia in humans.

Structure and Function of Enzymes of the Leloir Pathway for Galactose Metabolism*

Recent advances in the understanding of the structure and function of the Leloir pathway are presented, highlighting their important metabolic role in normal galactose metabolism.

Sugar recognition by human galactokinase

The sugar specificity of the enzyme and the kinetic consequences of mutating residues in the sugar-binding site are investigated in order to improve the understanding of substrate recognition by this enzyme.

Functional analysis of disease-causing mutations in human galactokinase.

Human galactokinase (GALK1) was expressed in and purified from Escherichia coli and product inhibition studies showed that the most likely kinetic mechanism of the enzyme was an ordered ternary complex one in which ATP is the first substrate to bind.

High Resolution X-ray Structure of Galactose Mutarotase from Lactococcus lactis *

The three-dimensional architecture of galactose mutarotase from Lactococcus lactis determined to 1.9-Å resolution is described, revealing a distinctive β-sandwich motif in each subunit and suggesting its possible role as a general acid/base group.

Creation of the first anomeric D/L-sugar kinase by means of directed evolution.

The application of directed evolution and a high-throughput multisugar colorimetric screen to enhance the catalytic capabilities of the Escherichia coli galactokinase GalK and compares the recently solved structure of Lactococcus lactis GalK to provide a blueprint for further engineering of this vital class of enzyme.