The structural and molecular biology of type III galactosemia

Timson, David J.

doi:10.1080/15216540600644846

Cited by 55 publications

(55 citation statements)

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“…Our data show that GalE knockdown leads to impaired insulin signaling and protein biosynthesis in hepatocytes, implying a potential mechanism for the essential role of GalE in cell survival. Since mammals, unlike unicellular organisms, are not critically dependent on an exogenous galactose supply, GalE transcription is not responsive to the presence of dietary galactose (27). Here, we demonstrate that GalE is transcriptionally regulated by Xbp1s.…”

Section: Figurementioning

confidence: 57%

The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Wang²,

et al. 2012

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Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes.

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Section: Figurementioning

confidence: 57%

The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Wang²,

et al. 2012

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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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“…17 GALE is a member of the short-chain dehydrogenase/reductase family of enzymes and is encoded by GALE, located on chromosome 1p36.11. In solution, GALE is a dimer and each subunit contains a binding site with one molecule of the cofactor NAD + .…”

Section: Galactokinasementioning

confidence: 99%

“…Several GALE variants associated with the three forms of GALE deficiency have been reported. 17,26 Newborn screening for galactosemia…”

Section: Gale Deficiency (Type III Galactosemia)mentioning

confidence: 99%