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.Background: Indonesia is one of developing country which still facing a serious problem concerning stunting.
Furthermore, the effect of GRE3 was independent of the inositol monophosphatases INM1 and INM2.
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. 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. 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. 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. In Saccharomyces cerevisiae, lithium induces a ‘galactosemia-like’ phenotype as a consequence of inhibition of phosphoglucomutase, a key enzyme in galactose metabolism. Figure The role of Thr28 and a water molecule in the local unfolding process around the point mutation of human galactokinase Based on the results, we propose a possible mechanism for the unfolding caused by the Pro28Thr point mutation. Local unfolding was verified by several other MD simulations performed with different duration, initial velocities and force field. Another consequence was the decrease in stability (5–7 kcal mol−1) around this region, as confirmed by ΔGbind calculations for the extracted part of the whole system. Altered H-bonding networks were detected based on geometric and electron density criteria that resulted in local unfolding of the β-sheet secondary structure. This paper reports a study of the Pro28Thr point mutation using a variety of theories including molecular dynamics (MD), MM-PBSA/GBSA calculations and AIM analysis.
Malfunctioning of galactokinase due to a single point mutation causes cataracts and, in serious cases, blindness. Galactokinase is responsible for the phosphorylation of α-d-galactose, which is an important step in the metabolism of the latter.
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