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The molecular basis of galactosemia - Past, present and future.
Gene. 2016 Sep 10; 589(2):133-41.GENE

Abstract

Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has 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.

Authors+Show Affiliations

School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK. Electronic address: d.timson@qub.ac.uk.

Pub Type(s)

Historical Article
Journal Article
Review

Language

eng

PubMed ID

26143117

Citation

Timson, David J.. "The Molecular Basis of Galactosemia - Past, Present and Future." Gene, vol. 589, no. 2, 2016, pp. 133-41.
Timson DJ. The molecular basis of galactosemia - Past, present and future. Gene. 2016;589(2):133-41.
Timson, D. J. (2016). The molecular basis of galactosemia - Past, present and future. Gene, 589(2), 133-41. https://doi.org/10.1016/j.gene.2015.06.077
Timson DJ. The Molecular Basis of Galactosemia - Past, Present and Future. Gene. 2016 Sep 10;589(2):133-41. PubMed PMID: 26143117.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular basis of galactosemia - Past, present and future. A1 - Timson,David J, Y1 - 2015/07/02/ PY - 2015/04/21/received PY - 2015/06/18/revised PY - 2015/06/29/accepted PY - 2015/7/6/entrez PY - 2015/7/6/pubmed PY - 2017/1/27/medline KW - Galactokinase KW - Galactose 1-phosphate uridylyltransferase KW - Inherited metabolic disease KW - Leloir pathway KW - UDP-galactose 4′-epimerase SP - 133 EP - 41 JF - Gene JO - Gene VL - 589 IS - 2 N2 - Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has 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. SN - 1879-0038 UR - https://www.unboundmedicine.com/medline/citation/26143117/The_molecular_basis_of_galactosemia___Past_present_and_future_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(15)00801-X DB - PRIME DP - Unbound Medicine ER -