Transcriptional, Proteomic, and Metabolic Responses to Lithium in Galactose-grown Yeast Cells

Abstract

Lithium is highly toxic to yeast when grown in galactose medium mainly because phosphoglucomutase, a key enzyme of galactose metabolism, is inhibited. We studied the global protein and gene expression profiles of Saccharomyces cerevisiae grown in galactose in different time intervals after addition of lithium. These results were related to physiological studies where both secreted and intracellular metabolites were determined. Microarray analysis showed that 664 open reading frames were down-regulated and 725 up-regulated in response to addition of lithium. Genes involved in transcription, translation, and nucleotide metabolism were down-regulated at the transcriptional level, whereas genes responsive to different stresses as well as genes from energy reserve metabolism and monosaccharide metabolism were up-regulated. Compared with the proteomic data, 26% of the down-regulated and 48% of the up-regulated proteins were also identified as being changed on the mRNA level. Functional clusters obtained from proteome data were coincident with transcriptional clusters. Physiological studies showed that acetate, glycerol, and glycogen accumulate in response to lithium, as reflected in expression data, whereas a change from respiro-fermentative to respiratory growth could not be predicted from the expression analyses.

Quantitative proteomics and transcriptomics of anaerobic and aerobic yeast cultures reveals post-transcriptional regulation of key cellular processes

“…Excellent reproducibility, and the option to manipulate individual culture parameters, make chemostat cultivation very well suited to quantitative systems biology research (Bro et al, 2003;Daran-Lapujade et al, 2004;Jansen et al, 2005;Kolkman et al, 2006). In particular, chemostat cultivation enables researchers to dissect effects of specific growth rate and of other parameters.…”

Development and application of proteomics technologies in Saccharomyces cerevisiae

“…This study revealed exclusively major changes in the central carbon metabolism pathways upon changing the carbon source. In other studies, 2D gel electrophoresis was used to obtain a global view of changes in the yeast proteome as a function of stimuli in the environment, such as cadmium [45], lithium [46], H 2 O 2 [47], sorbic acid [48] and amino acid starvation [49].…”

Erythrocyte phosphoglucomutase activity of bipolar I patients currently using lithium or carbamazepine

“…Although it has not been tested if bipolar disorder is linked to any metabolic disorder regulated by phosphoglucomutase, inhibition of this enzyme by lithium would probably lead to galactosemia and poor glycogen turnover, as has been shown in yeast (8). A recent report has shown that phosphoglucomutase activity is up-regulated in leukocytes from lithium-treated patients, even though lithium inhibits phosphoglucomutase activity in vitro (10). In the present study, we determined the distribution of phosphoglucomutase activity in erythrocytes from control, lithiumtreated and carbamazepine-treated subjects, in order to determine if differences in phosphoglucomutase activity are linked to bipolar disorder.…”

“…Inhibition of phosphoglucomutase by lithium in yeast cells has drastic effects on carbohydrate metabolism. During glucose metabolism lithium reduces the steady-state levels of UDP-glucose, resulting in a defect of glycogen and trehalose biosynthesis, while galactose metabolism is inhibited, leading to galactosemia, accumulation of galactose-1P and Glu 1-P and inhibition of fermentation (8,10). A recent report has shown that lithium treatment up-regulates phosphoglucomutase activity in various tissues of the rat and in bipolar patients, even though lithium inhibits phosphoglucomutase activity in vitro (11).…”