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-3-phosphate dehydrogenase enzymes in yeast, by S-thiolation, KRX-0401 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, the first downstream enzyme of TPI in glycolysis, GAPDH, is specifically inactivated after peroxide treatment of yeast cells and this subject is,Crizotinib 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. Several studies demonstrated an allelic frequency from roughly 0.002 to 0.02. Indeed this number implies that 1 out of 2000 newborn individuals from the latter population would suffer from this tremendous disorder, but less than 100 individuals have been diagnosed with TPI deficiency worldwide. A mutagenesis screen in mice identified four heterozygous TPI mutations that lead to a 50% reduction in catalytic TPI activity in several tissues examined.