UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster.
UDP-galactose 4' epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose in the final step of the Leloir pathway; human GALE (hGALE) also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. GALE therefore plays key roles in the metabolism of dietary galactose, in the production of endogenous galactose, and in maintaining the ratios of key substrates for glycoprotein and glycolipid biosynthesis. Partial impairment of hGALE results in the potentially lethal disorder epimerase-deficiency galactosemia. We report here the generation and initial characterization of a first whole-animal model of GALE deficiency using the fruit fly Drosophila melanogaster. Our results confirm that GALE function is essential in developing animals; Drosophila lacking GALE die as embryos but are rescued by the expression of a human GALE transgene. Larvae in which GALE has been conditionally knocked down die within days of GALE loss. Conditional knockdown and transgene expression studies further demonstrate that GALE expression in the gut primordium and Malpighian tubules is both necessary and sufficient for survival. Finally, like patients with generalized epimerase deficiency galactosemia, Drosophila with partial GALE loss survive in the absence of galactose but succumb in development if exposed to dietary galactose. These data establish the utility of the fly model of GALE deficiency and set the stage for future studies to define the mechanism(s) and modifiers of outcome in epimerase deficiency galactosemia.
Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, GA 30322, USA.
Rebecca D
RD
Sanders
Jennifer M I
JM
Sefton
Kenneth H
KH
Moberg
Judith L
JL
Fridovich-Keil
D000483:Alleles; D000818:Animals; D004331:Drosophila melanogaster / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005690:Galactose / Q000378:metabolism / Q000494:pharmacology; D005695:Galactosephosphates / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008317:Malpighian Tubules / Q000187:drug effects / Q000201:enzymology; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D014534:UDPglucose 4-Epimerase / Q000378:metabolism*
D005695:Galactosephosphates; C029973:galactose-1-phosphate; D014534:UDPglucose 4-Epimerase; D005690:Galactose