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Author Notes:

Corresponding author: Judith L. Fridovich-Keil, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America. Email: jfridov@emory.edu.

Conceived and designed the experiments: JLF-K JMID RDS. Performed the experiments: JMID RDS DH. Analyzed the data: JMID RDS DH JLF-K. Wrote the paper: JLF-K JMID RDS DH.

We thank members of the Departments of Human Genetics and Cell Biology and Biology at Emory University for many helpful discussions concerning this project.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

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Research Funding:

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.

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

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PLoS Genetics

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Volume 8, Number 5

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Article | Final Publisher PDF

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.

Copyright information:

© 2012 Daenzer et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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