title: The galactose-induced decrease in phosphate levels leads to toxicity in yeast models of galactosemia.
abstract: Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease.
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Caio M
authors.initials: CM
authors.lastname: Machado
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Evandro A
authors.initials: EA
authors.lastname: De-Souza
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Ana Luiza F V
authors.initials: ALFV
authors.lastname: De-Queiroz
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Felipe S A
authors.initials: FSA
authors.lastname: Pimentel
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Guilherme F S
authors.initials: GFS
authors.lastname: Silva
authors.affiliation: Laboratório de Entomologia Médica, Programa de Biologia Celular e Parasitologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Gomes
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Mónica
authors.initials: M
authors.lastname: Montero-Lomelí
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil. Electronic address: cmasuda@bioqmed.ufrj.br.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Masuda
mesh_terms: D005686:Galactokinase / Q000235:genetics / Q000378:metabolism; D005690:Galactose / Q000378:metabolism / Q000494:pharmacology; D005693:Galactosemias / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010710:Phosphates / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D010710:Phosphates; D029701:Saccharomyces cerevisiae Proteins; D006003:Glycogen; C524219:GAL1 protein, S cerevisiae; D005686:Galactokinase; D005690:Galactose
keywords: Galactose-1-phosphate; Galactosemia; Lithium; Phosphate trapping; Saccharomyces cerevisiae; Unfolded protein response