UDP-galactose 4′ epimerase (GALE) is essential for development of<i>Drosophila melanogaster</i>

Sanders, Rebecca; Sefton, Jennifer M. I.; Moberg, Kenneth H.; Fridovich‐Keil, Judith L.

doi:10.1242/dmm.005058

Cited by 43 publications

(65 citation statements)

References 41 publications

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“…Whereas loss-of-function mutations in GalT or GalK, the other two genes of the Leloir pathway, have been described (23,24), no cases of functional GalE-null mutants have been reported (25). Consistent with the essential nature of this enzyme, the GalE-deficient fruit fly is developmentally lethal (26). 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.…”

Section: Figurementioning

confidence: 99%

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: 99%

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

Wang²,

et al. 2012

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“…Reactive oxygen species are also implicated in the formation of galactosemic cataracts (Mulhern et al , 2006;Mulhern et al , 2007;Abdul Nasir et al , 2014). D. melanogaster and Caenorhabditis elegans models of type III galactosemia have also been developed (Sanders et al , 2010;Brokate-Llanos et al , 2014). The fruit fly model demonstrated that GALE is essential for development of the organism (Sanders et al , 2010).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…D. melanogaster and Caenorhabditis elegans models of type III galactosemia have also been developed (Sanders et al , 2010;Brokate-Llanos et al , 2014). The fruit fly model demonstrated that GALE is essential for development of the organism (Sanders et al , 2010). It also demonstrated that the two physiologically important activities of GALE (epimerisation of UDP-galactose and UDP-N-acetylgalactosamine) were vital and played different roles in development (Daenzer et al , 2012).…”

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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“…Some variant GALE proteins are catalytically impaired, while others demonstrate compromised stability, at least under defined laboratory conditions. While the relationship between GALE activity and galactose-sensitivity has been defined in yeast and Drosophila models (Sanders et al 2010;Wasilenko and Fridovich-Keil 2006), the relationship between GALE activity level and outcome severity in patients remains a point of speculation.…”

Section: Introductionmentioning

confidence: 99%

A Case Study of Monozygotic Twins Apparently Homozygous for a Novel Variant of UDP-Galactose 4′-epimerase (GALE)

et al. 2012

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Epimerase deficiency galactosemia is an autosomal recessive disorder that results from partial impairment of UDP-galactose 4 0 -epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism. Clinical severity of epimerase deficiency ranges from potentially lethal to apparently benign, likely reflecting the extent of GALE enzyme impairment, among other factors. We report here a case study of monozygotic twins identified by newborn screening with elevated total galactose and normal galactose-1P uridylyltransferase (GALT). Follow-up testing revealed partial impairment of GALE in hemolysates but near-normal activity in lymphoblasts; molecular testing identified a missense substitution, R220W, apparently in the homozygous state. The twins were treated with dietary galactose restriction for the first 18 months of life. During this time, independent testing revealed concurrent diagnoses of Williams Syndrome in both twins, and cytomegalovirus (CMV) infection in one. Expression studies of R220W-hGALE in a null-background strain of Saccharomyces cerevisiae demonstrated a very limited impairment of

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UDP-galactose 4′ epimerase (GALE) is essential for development ofDrosophila melanogaster

Cited by 43 publications

References 41 publications

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

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

The molecular basis of galactosemia — Past, present and future

A Case Study of Monozygotic Twins Apparently Homozygous for a Novel Variant of UDP-Galactose 4′-epimerase (GALE)

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