Overexpression of the aldose reductase GRE3 suppresses lithium-induced galactose toxicity in Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, lithium induces a 'galactosemia-like' phenotype as a consequence of inhibition of phosphoglucomutase, a key enzyme in galactose metabolism. Induced galactose toxicity is prevented by deletion of GAL4, which inhibits the transcriptional activation of genes involved in galactose metabolism and by deletion of the galactokinase (GAL1), indicating that galactose-1-phosphate, a phosphorylated intermediate of the Leloir pathway, is the toxic compound. As an alternative to inhibiting entry and metabolism of galactose, we investigated whether deviation of galactose metabolism from the Leloir pathway would also overcome the galactosemic effect of lithium. We show that cells overexpressing the aldose reductase GRE3, which converts galactose to galactitol, are more tolerant to lithium than wild-type cells when grown in galactose medium and they accumulate more galactitol and less galactose-1-phosphate. Overexpression of GRE3 also suppressed the galactose growth defect of the 'galactosemic'gal7- and gal10-deleted strains, which lack galactose-1-P-uridyltransferase or UDP-galactose-4-epimerase activities, respectively. Furthermore, the effect of GRE3 was independent of the inositol monophosphatases INM1 and INM2. We propose that lithium induces a galactosemic state in yeast and that inhibition of the Leloir pathway before the phosphorylation step or stimulation of galactitol production suppresses lithium-induced galactose toxicity.
Masuda
Claudio A
CA
Instituto de Bioquímica Médica, Programa de Biotecnologia e Biologia Molecular, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Brazil.
Previato
Jose O
JO
Miranda
Michel N
MN
Assis
Leandro J
LJ
Penha
Luciana L
LL
Mendonça-Previato
Lucia
L
Montero-Lomelí
Mónica
M
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D018692:Antimanic Agents / Q000494:pharmacology*; D005686:Galactokinase / Q000235:genetics / Q000378:metabolism; D005690:Galactose / Q000378:metabolism / Q000633:toxicity; D005695:Galactosephosphates / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D008094:Lithium / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D018692:Antimanic Agents; D005695:Galactosephosphates; D029701:Saccharomyces cerevisiae Proteins; C029973:galactose-1-phosphate; D008094:Lithium; D000449:Aldehyde Reductase; D005686:Galactokinase; D005690:Galactose