Abstract
In both humans and Drosophila melanogaster, UDP-galactose 4′-epimerase (GALE) catalyzes two distinct reactions, interconverting UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc) in the final step of the Leloir pathway of galactose metabolism, and also interconverting UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc). All four of these UDP-sugars serve as vital substrates for glycosylation in metazoans. Partial loss of GALE in humans results in the spectrum disorder epimerase deficiency galactosemia; partial loss of GALE in Drosophila melanogaster also results in galactose-sensitivity, and complete loss in Drosophila is embryonic lethal. However, whether these outcomes in both humans and flies result from loss of one GALE activity, the other, or both has remained unknown. To address this question, we uncoupled the two activities in a Drosophila model, effectively replacing the endogenous dGALE with prokaryotic transgenes, one of which (Escherichia coli GALE) efficiently interconverts only UDP-gal/UDP-glc, and the other of which (Plesiomonas shigelloides wbgU) efficiently interconverts only UDP-galNAc/UDP-glcNAc. Our results demonstrate that both UDP-gal and UDP-galNAc activities of dGALE are required for Drosophila survival, although distinct roles for each activity can be seen in specific windows of developmental time or in response to a galactose challenge. By extension, these data also suggest that both activities might play distinct and essential roles in humans.
Highlights
Galactose is an essential component of glycoproteins and glycolipids in metazoans, and as a constituent monosaccharide of the milk sugar, lactose, serves as a key nutrient for mammalian infants
The reactions of the Leloir pathway are catalyzed by the sequential activities of three enzymes: (1) galactokinase (GALK) which phosphorylates alpha-D-galactose to form galactose-1phosphate, (2) galactose-1-phosphate uridylyltransferase (GALT), which transfers uridine monophosphate (UMP) from uridine diphosphoglucose (UDP-glc) to gal-1P, forming UDPgalactose (UDP-gal) and releasing glucose-1-phosphate, which can proceed to phosphoglucomutase and the glycolytic pathway, and (3) UDP-galactose 49-epimerase (GALE) which interconverts UDP-gal and UDP-glc [1]
Author Summary In this manuscript we apply a fruit fly model to explore the relative contributions of each of two different activities attributed to a single enzyme—UDP-galactose 49-epimerase (GALE); partial impairment of human GALE results in the potentially severe metabolic disorder epimerase deficiency galactosemia
Summary
Galactose is an essential component of glycoproteins and glycolipids in metazoans, and as a constituent monosaccharide of the milk sugar, lactose, serves as a key nutrient for mammalian infants. Galactose is found in notable quantities in some fruits, vegetables, and legumes. Galactose is both synthesized and catabolized in all species via the Leloir pathway, which is highly conserved across branches of the evolutionary tree [1]. In addition to a role in the Leloir pathway, metazoan GALE enzymes interconvert UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc) (Figure 1). Because it catalyzes reversible reactions, GALE contributes to the catabolism of dietary galactose, and enables the endogenous biosynthesis of both UDP-gal and UDP-galNAc [2,3] when exogenous sources are limited
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