Structural and molecular biology of type I galactosemia: Disease‐associated mutations

McCorvie, Thomas J.; Timson, David J.

doi:10.1002/iub.510

Cited by 35 publications

(25 citation statements)

References 44 publications

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“…More sophisticated tools, such as molecular dynamic simulation protocols should allow refining structural data, particularly in compound heterozygotes. The possibility that the Leloir pathway enzymes may form a multienzyme complex with protein-protein interactions and coordinated regulation of the genes encoding the protein has also to be explored [56] as well as how does the clinical phenotype evolve over time [55].…”

Section: Discussionmentioning

confidence: 99%

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

Boutron

Marabotti

Facchiano

et al. 2012

Molecular Genetics and Metabolism

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Section: Discussionmentioning

confidence: 99%

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

Boutron

Marabotti

Facchiano

et al. 2012

Molecular Genetics and Metabolism

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“…M. Flanagan et al , 2010;Coss et al , 2013). This disease results from mutations in the gene encoding galactose 1-phosphate uridylyltransferase (GALT; EC 2.7.7.12) (Leslie et al , 1992;Tyfield et al , 1999;T. J. McCorvie & Timson , 2011a;T.…”

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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“…These diseases tend to be rare, but the symptoms are often severe. Examples include triose phosphate isomerase deficiency (OMIM #615512), phosphoglycerate kinase 1 deficiency (OMIM # 300653), hereditary fructose intolerance (aldolase B deficiency; OMIM #22960) and classic galactosemia (galactose 1-phosphate uridylyltransferase deficiency; OMIM #230400) [27][28][29][30][31]. In addition to reduced energy production, these diseases often have additional phenotypes.…”

Section: The Potentials and Pitfalls Of Targeting Metabolic Enzymesmentioning

confidence: 99%

Metabolic enzymes of helminth parasites: potential as drug targets

Timson¹

2015

CPPS

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Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

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Structural and molecular biology of type I galactosemia: Disease‐associated mutations

Cited by 35 publications

References 44 publications

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations

The molecular basis of galactosemia — Past, present and future

Metabolic enzymes of helminth parasites: potential as drug targets

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