UDP-Galactose-4-Epimerase (GALE)

McCorvie, Thomas J.; Timson, David J.

doi:10.1007/978-4-431-54240-7_21

Cited by 8 publications

(9 citation statements)

References 70 publications

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“…It contains a bound NAD þ as an essential cofactor, which is thought to transiently oxidize the sugar moiety at carbon-4 and then re-reduces it in a nonstereospecific manner, permitting inversion of configuration [19].…”

Section: Key Pointsmentioning

confidence: 99%

Galactose metabolism and health

Coelho

Berry

Rubio-Gozalbo

2015

Current Opinion in Clinical Nutrition and Metabolic Care

179

116

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Section: Key Pointsmentioning

confidence: 99%

Galactose metabolism and health

Coelho

Berry

Rubio-Gozalbo

2015

Current Opinion in Clinical Nutrition and Metabolic Care

179

116

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“…Of the three types of galactosemia, type III has the smallest number (~25) of identified disease-associated mutations (Timson , 2006;T. J. McCorvie & Timson , 2014).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

The molecular basis of galactosemia — Past, present and future

Timson

2016

Gene

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Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100 years have seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies.Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins.

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“…In many organisms, including humans, the enzyme can also catalyze the interconversion of the N-acetylated forms of these UDP-sugars (2). The reaction with UDP-galactose is important because it plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate (3, 4).…”

Section: Introductionmentioning

confidence: 99%

Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase—A computational perspective on severe epimerase-deficiency galactosemia

Timson

Lindert

2013

Gene

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UDP-galactose 4′-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr-157) and the enzyme-bound NAD+ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (kcat), with less substantial effects on Km. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N-acetylgalactosemine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia.

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UDP-Galactose-4-Epimerase (GALE)

Cited by 8 publications

References 70 publications

Galactose metabolism and health

Galactose metabolism and health

The molecular basis of galactosemia — Past, present and future

Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase—A computational perspective on severe epimerase-deficiency galactosemia

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