Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition

Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors.     

Some Tests for k£2 Upper Outliers in an Exponential Sample

The sequential procedure for testing up to k upper outliers proposed by Kimber (1982) for one-parameter exponential distribution is modified to a two-parameter exponential distribution. Further null distributions of some test statistics for an upper outlier-pair in a complete or censored sample from a two-parameter exponential distribution are given. Percentage points of the statistic T₁ are tabulated.     

Induction of cellulase in trichoderma reesei grown on lactose

Intracellular concentrations of ATP, cyclic AMP and glucose-6-phosphate were monitored during growth of partially catabolically derepressed strain of Trichoderma reesei CC II in medium containing lactose as the sole carbon source. The induction of cellulase synthesis occured when the concentration of lactose in the medium decreased below 7 mg/ml. The onset of cellulase synthesis was preceded by a transient peak of intracellular concentration of ATP and by the increase of the cyclic AMP contents in the mycelium whereby the intracellular level of glucose-6-phosphate was at its minimum. By keeping the lactose concentration in the medium at 2 mg/ml, it was possible to support the continuation of cellulase synthesis over the prolonged periods without appreciable growth of biomass.     

Effect of precursors on biosynthesis of monensins A and B

Precursors of monensins (acetate, propionate, butyrate, isobutyrate) affect the total production and the relative proportion of monensins A and B. Addition of propionate into the fermentation medium causes a prevalence of monensin B whereas butyrate and isobutyrate stimulate the production of monensin A and suppress the production of monensin B.