title: The C. elegans lethal gut-obstructed gob-1 gene is trehalose-6-phosphate phosphatase.
abstract: We identified the gob-1 (gut-obstructed) gene in a forward genetic screen for intestinal defects in the nematode Caenorhabditis elegans. gob-1 loss of function results in early larval lethality, at least in part because of a blocked intestinal lumen and consequent starvation. The gob-1 gene is first expressed in the 8E cell stage of the embryonic intestine, and the GATA factor ELT-2 is sufficient but not necessary for this early phase of gob-1 expression; gob-1 expression later becomes widespread in embryos, larvae, and adults. GOB-1 is a member of the HAD-like hydrolase superfamily and shows a robust and specific phosphatase activity for the substrate trehalose-6-phosphate. Trehalose is a glucose disaccharide found in bacteria, fungi, plants, insects, and nematodes but not in mammals. Trehalose plays a number of critical roles such as providing flexible energy reserves and contributing to thermal and osmotic stress resistance. In budding yeast and in plants, the intermediate in trehalose synthesis, trehalose-6-phosphate, has additional critical but less well-defined roles in controlling glycolysis and carbohydrate metabolism. Strong loss-of-function mutants in the C. elegans tps-1 and tps-2 genes (which encode the two trehalose phosphate synthases responsible for trehalose-6-phosphate synthesis) completely suppress the lethality associated with gob-1 loss of function. The suppression of gob-1 lethality by ablation of TPS-1 and TPS-2, the upstream enzymes in the trehalose synthesis pathway, suggests that gob-1 lethality results from a toxic build-up of the intermediate trehalose-6-phosphate, not from an absence of trehalose. GOB-1 is the first trehalose-6-phosphate phosphatase to be identified in nematodes and, because of its associated lethality and distinctive sequence properties, provides a new and attractive target for anti-parasitic drugs.
authors.affiliation: Department of Biochemistry and Molecular Biology, Genes and Development Research Group, University of Calgary Faculty of Medicine, Health Sciences Centre, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Kormish
authors.forename: James D
authors.initials: JD
authors.lastname: McGhee
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000201:enzymology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050980:GATA Transcription Factors / Q000502:physiology; D005804:Genes, Lethal; D006867:Hydrolases / Q000235:genetics; D007415:Intestinal Obstruction / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007422:Intestines / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D029742:Caenorhabditis elegans Proteins; C094134:ELT-2 protein, C elegans; D050980:GATA Transcription Factors; D006867:Hydrolases; C023178:trehalose-phosphatase; D010744:Phosphoric Monoester Hydrolases; C034507:2-haloacid dehalogenase