Ribonucleases: From Prototypes to Therapeutic Targets? (General Articles)
Ribonucleases (RNases) have proven to be excellent model systems for the study of protein structure, folding and stability, and enzyme catalysis, resulting in four Nobel Prize lectures in chemistry. Beside this ‘academic’ success, RNases are also relevant from a medical point of view. The RNA population in cells is controlled post-transcriptionally by ribonucleases (RNases) of varying specificity. Other therapeutic proteins like angiogenin, neurotoxins, and plant allergens have RNase activity or significant structural homology to known RNases. Also, RNase activity in serum and cell extracts is elevated in a variety of cancers and infectious diseases. To date, no clinical drugs are available that target this important class of enzymes. Small-molecule RNase inhibitors derived from mono- or dinucleotides, as well as pentavalent oxyvanadate transition state analogs are found to be rather marginal inhibitors. These compounds bind their target RNase with dissociation constants in the micromolar range, whereas transition state theory predicts picomolar values for genuine transition states. The rational design for new transition state analog inhibitors requires knowledge of the precise nature of the transition state and of the occurring intermolecular enzyme-substrate interactions. This review focuses on these chemical and structural features of RNase A and RNase T1, the best characterized members of two separate classes of ribonucleases.
Document Type: Review Article
Publication date: 2003-05-01
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