Functional analysis of disease‐causing mutations in human UDP‐galactose 4‐epimerase

Timson, David J.

doi:10.1111/j.1742-4658.2005.05017.x

Cited by 47 publications

(95 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surface exposed mutations might be assumed to affect protein-protein interactions. However, none are located in the interface between the monomers of the GALE dimer and none of the mutant proteins tested showed any defect in dimerization (30). Furthermore it is possible that a failure to dimerize would not affect the enzyme's activity greatly: monomers of the E. coli enzyme appear to be almost as active as the dimer (32).…”

Section: Structural Correlations Of Disease-causing Mutantsmentioning

confidence: 99%

“…In some cases, e.g., L183P which introduces the conformationally constrained proline into a b-sheet in the interior of the protein, it is easy to see why the mutation will result in impaired function. Indeed, in this case the mutant protein is highly susceptible to proteolysis (30). In other cases, the cause is less clear and only detailed structural or modelling studies are likely to reveal the links between sequence changes and reduction in enzymic activity.…”

Section: Structural Correlations Of Disease-causing Mutantsmentioning

confidence: 99%

“…The image was generated with PyMol using PDB files 1EK6 (wild type) (13) and 1I3L (mutant) (15). No isolated enzyme studied so far has shown a change in K m for UDP-galactose greater than threefold (30,31); GALE activity and k cat values refer to activity with UDP-galactose unless otherwise stated. nd, not determined.…”

Section: Therapies and Treatmentsmentioning

confidence: 99%

“…This reduced stability results in a higher susceptibility of some mutant proteins to limited proteolytic digestion in vitro and to decreased amounts of intact protein in vivo (29,30). The mutation associated with the generalized form of the disease, V94M, has one of the most impaired turnover numbers (of the mutations so far characterized), but does not appear to be less stable than the wild type (as judged by limited proteolysis) (7,30,31). A fuller understanding of the relationship between the functional effects of the mutations and disease-causation is not possible due to two factors -the relatively small numbers of patients characterized and the fact that many galactosemic individuals are heterozygotes.…”

Section: Mutations In Udp-galactose 4-epimerase Associated With Type mentioning

confidence: 99%

See 3 more Smart Citations

The structural and molecular biology of type III galactosemia

Timson¹

2006

IUBMB Life (International Union of Biochemistry and Molecular B

View full text Add to dashboard Cite

SummaryType III galactosemia is a genetic disease caused by mutations in the gene encoding UDP-galactose 4-epimerase. A variety of different point mutations located throughout the gene can be responsible. The main, disease-causing effects of these mutations appear to be a reduction in the catalytic rate constant (k cat ) and an increase in the proteolytic sensitivity of the protein. Many of the mutations are distant from the active site of the enzyme and therefore must be assumed to affect the overall fold of the protein.Although the disease was previously classified into a severe, or generalized, form and an essentially benign, or peripheral, form this distinction has been blurred by recent work. Instead of two separate conditions it now appears that type III galactosemia is a continuum and that the symptoms will vary depending on the mutation(s) carried by the individual sufferer. This new way of looking at the disease has implications for the treatment and long term monitoring of patients. IUBMB Life, 58: 83 -89, 2006 Keywords Leloir pathway; UDP-galactose 4-epimerase; GALE; genetic disease; galactose; short-chain dehydrogenase/ reductase.Abbreviations GALM, Galactose mutarotase; GALK1, galactokinase; GALT, galactose-1-phosphate uridyltransferase; GALE, UDP-galactose 4-epimerase; SDR, the short-chain dehydrogenase/reductase; k cat , the catalytic rate constant or turnover number; K m , the Michaelis constant.

show abstract

Section: Structural Correlations Of Disease-causing Mutantsmentioning

confidence: 99%

Section: Structural Correlations Of Disease-causing Mutantsmentioning

confidence: 99%

Section: Therapies and Treatmentsmentioning

confidence: 99%

Section: Mutations In Udp-galactose 4-epimerase Associated With Type mentioning

confidence: 99%

See 2 more Smart Citations

The structural and molecular biology of type III galactosemia

Timson¹

2006

IUBMB Life (International Union of Biochemistry and Molecular B

View full text Add to dashboard Cite

show abstract

“…11 severe forms of the disease Timson , 2005 Although studies on isolated enzymes have been useful for understanding the fundamental, molecular basis of the disease, it is also necessary to understand the effects on cells, organs and whole organisms. Over the years, the budding yeast S. cerevisiae has proved to be a useful model system for studying both type I and type III galactosemia (Wells & Fridovich-Keil , 1996).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

The molecular basis of galactosemia — Past, present and future

Timson

2016

Gene

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Molecular Genetics of Galactosaemia

Lai

Mao

2012

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

The three different enzymes of galactose metabolism (galactokinase, galactose‐1‐phosphate uridyltransferase, UDP‐galactose‐4‐epimerase) can be impaired by genetic alterations, leading to three different forms of the genetic disease, galactosaemia. Their clinical outcome can vary from very mild to lethal depending on the enzyme involved, and on the respective gene mutations, but a clear‐cut correlation between genotype and phenotype of patients is not yet known. Understanding the molecular genetics of galactosaemia is essential to correlate the genotype of the patients to their phenotype, and eventually to their clinical outcome. The prediction of the effects of genetic alterations on enzyme structure and functions is just the first step of the long journey towards the final scope: to render clinicians and scientific community the tools to predict the effect of a galactosaemia‐linked mutation on the future quality of life of an affected newborn, in order to provide the best personalised solutions for the treatment. Key Concepts: Disorders in galactose metabolism in humans caused by hereditary deficiencies of the enzymes in the Leloir pathway can lead to severe and potentially lethal diseases called galactosaemia. Depending on the specific enzyme that is deficient, three types of galactosaemia (Type I, II and III) with varying severity can occur. Newborn screening programmes for galactosaemia are implemented in many developed countries to prevent acute lethality in the affected neonates. The genes encoding the enzymes associated with all types of galactosaemia have been isolated, allowing the determination of the deleterious changes leading to the diseases. Many of the variations seen in the GAL genes are private in nature, although specific changes are prevalent in different ethnic populations.

show abstract

Functional analysis of disease‐causing mutations in human UDP‐galactose 4‐epimerase

Cited by 47 publications

References 40 publications

The structural and molecular biology of type III galactosemia

The structural and molecular biology of type III galactosemia

The molecular basis of galactosemia — Past, present and future

Molecular Genetics of Galactosaemia

Contact Info

Product

Resources

About