ENZYME CATALYSIS

The mechanisms by which enzymes catalyze reactions are of interest from a purely scientific, physical organic perspective, but also from an applied point of view: understanding an enzyme mechanism has implications for inhibitor design and potentially, rational drug design. Two nucleotide-related reactions that are particularly suitable for directed computational and gas-phase experimental studies are the decarboxylation of orotidine 5'-monophosphate (OMP) and the cleavage of an erroneously inserted uracil in DNA. The decarboxylation of OMP is catalyzed by a highly proficient enzyme, OMP decarboxylase; the mechanism remains unknown. Computational and experimental studies are used to uncover the mechanisms by which the enzyme can effect catalysis. Uracil-DNA glycosylases cleave the uracil-ribose bond in DNA (where a deoxyuridine has been erroneously inserted). The study of the mechanism can be reduced to a question of the acidity of uracil. The effects of protonation and nearby cations on uracil acidity are currently being explored computationally, while the gas-phase acidity of uracil is being examined experimentally.