Previous studies within our group have yielded a class of cinnamoyl-based competitive reversible inhibitors for tissue transglutaminase (TG2), with values as low as 1.0 μM (compound). However, due to the electrophilic nature of their alkene moiety, this class of inhibitors is susceptible to nucleophilic attack by glutathione, a key element in cellular metabolism and toxicity response. To address this issue, we made several modifications to the inhibitor scaffold, ultimately showing that a bis(triazole) scaffold increased resistance to nucleophilic attack, with compound being the most potent ( = 10 μM). In the process of reducing reactivity, we also prepared a new class of inhibitors, replacing the alkene of with an alkyne, leading to a significant increase in potency for compound ( = 420 nM).
Résumé : Les conversions géniques sont des échanges non réciproques de séquences entre gènes. Elles sont relativement fréquentes chez Saccharomyces cerevisiae, mais peu d'études ont analysé le destin évolutif des conversions géniques ou leur impact fonctionnel chez les gènes de levures. Ici, nous analysons l'évolution et l'impact des conversions géniques entre les deux gènes codant pour la phosphatase du 2-déoxyglucose-6-phosphate chez S. cerevisiae, Saccharomyces paradoxus et Saccharomyces mikatae. Nos résultats démontrent que la dernière moitié de ces gènes est sujette à des conversions géniques chez ces trois espèces. La grande similarité et le plus grand pourcentage de nucléotides G et C dans les régions converties, ainsi que l'absence de longues régions de sites convertis communs adjacents, suggèrent que ces conversions géniques se produisent fréquemment et de façon indépendante chez ces trois espèces. La haute fréquence de ces conversions résulte probablement du fait qu'elles ont peu d'impact sur les séquences protéiques codées par ces gènes.
Mots-clés :Saccharomyce cerevisiae, Saccharomyces paradoxus, Saccharomyces mikatae, conversions géniques, phosphatase du 2-déoxyglucose 6-phosphate.Abstract: Gene conversions are nonreciprocal sequence exchanges between genes. They are relatively common in Saccharomyces cerevisiae, but few studies have investigated the evolutionary fate of gene conversions or their functional impacts. Here, we analyze the evolution and impact of gene conversions between the two genes encoding 2-deoxyglucose-6-phosphate phosphatase in S. cerevisiae, Saccharomyces paradoxus and Saccharomyces mikatae. Our results demonstrate that the last half of these genes are subject to gene conversions among these three species. The greater similarity and the greater percentage of GC nucleotides in the converted regions, as well as the absence of long regions of adjacent common converted sites, suggest that these gene conversions are frequent and occur independently in all three species. The high frequency of these conversions probably result from the fact that they have little impact on the protein sequences encoded by these genes.
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