UDP-Galactose 4′-Epimerase Activities toward UDP-Gal and UDP-GalNAc Play Different Roles in the Development of Drosophila melanogaster

• Type of Material: Article
• Authors: Jennifer M. I. Daenzer, Emory University; Rebecca D. Sanders, Emory University; Darwin Hang, Emory University; Judith Fridovich-Keil, Emory University
• Language: English
• Date: 2012-05
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Daenzer et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002721
• Title of Journal or Parent Work: PLoS Genetics
• Volume: 8
• Issue: 5
• Grant/Funding Information: This work was funded by NIH grant DK046403 (to JLF-K), National Institutes of Health Training Program in Human Disease Genetics grant 1T32MH087977, and National Institutes of Health Training grant T32GM08490-16.
• Research Categories: Biology, Genetics; Biology, Molecular

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.