In the light of these results, it is quite remarkable that the Glu104Asp TPI variant, which displayed the most modified dimerization behavior, is the most common variant observed amongst the affected individuals. Moreover, this variant is the only TPI variant found homozygous among affected individuals; all other mutations occur only in the compound heterozygous state together with the Glu104Asp variant or with an obvious TPI null allele. For example, in the TPI Paris family, the start codon mutant has been detected in the heterozygous state with the Glu104Asp variant, the Phe240Leu variant observed in the Hungarian family is found together with the Glu145TER null allele. Generally, dimerization between Labetalol hydrochloride proteins is a substantial process to generate and regulate cellular functions of proteins. Remarkably, we discovered that overexpression of the Glu104Asp variant results in 4-(Benzyloxy)phenol reduced levels of endogenous TPI in mammalian cells. This finding is exciting since recent studies demonstrated that both compound heterozygous brothers of the Hungarian family have reduced TPI mRNA levels compared to their parents and healthy controls suggesting that altered dimer formation resulting in a modified feedback regulation of the TPI enzyme could underlie the pathogenesis of TPI deficiency. Remarkably, TPI is highly up-regulated under stress conditions in mammalian cells. Regarding this issue, it is important that expression of the Ile170Val TPI variant with reduced catalytic activity results in higher resistance of yeast to diamide. Diamide is an oxidant which is known to stoichiometrically oxidize small molecules including glutathione within red 
blood cells, but is less effective in oxidizing protein-integrated cysteines. Therefore, diamide treatment results in a rapid decrease in intracellular GSH, thus, leading to oxidative stress. Interestingly, the response mechanisms of eukaryotic cells to oxidative stress are strictly dependent on the compound and its downstream effects. This might explain why yeast cells expressing the TPI variant with reduced catalytic activity were not resistant to all oxidants examined. It is noteworthy to mention that in contrast to diamide, all other oxidants used in this study are hydroperoxides. Treatment with hydroperoxides leads to the inactivation of the Tdh3 protein, the most abundant of the three glyceraldehyde-3phosphate dehydrogenase enzymes in yeast, by Sthiolation, carbonlyation or ADP-ribosylation. GAPDH catalyzes the first downstream reaction after TPI in glycolysis and remarkably, mutants lacking TDH3 were sensitive to a challenge with a lethal dose of H2O2. It is likely that inactivation of GAPDH after peroxide treatment of yeast cells is forestalling the protective effect of TPI variants exhibiting reduced catalytic activity. In this context it is noteworthy to mention that blockage of glycolysis can force an increased influx of metabolites into the pentose phosphate pathway resulting in an elevated cellular NADPH concentration and vice-versa that different mutations introduced in enzymes implicated in this pathway are leading to oxidant-hypersensitive cells. High intracellular NADPH levels are beneficial during conditions of oxidative stress, because NADPH provides the base for several antioxidant enzymes including the thioredoxins or the glutaredoxin system. As aforementioned GAPDH, is specifically inactivated after peroxide treatment of yeast cells and this subject is, interestingly, reflected in mammalian cells as well. In the light of the above-mentioned findings it is quite intriguing that the frequency of heterozygous individuals carrying one inactive TPI allele is quite high.