Transition state analogues for enzymes of nucleic acid metabolism.
Knowledge of enzymatic transition states permits the logical design of transition state analogues. Kinetic isotope effects have been used to solve transition state structures for several N-ribosyltransferases. Nucleoside hydrolases from protozoan parasites show ribooxacarbenium ion character at their transition states, but with different extents of activation at the leaving group and the oxacarbenium ion. Transition state analogues are designed to capture these interactions and provide isozyme-specific inhibitors. Ricin A-chain is an RNA N-ribohydrolase for a single site on 28S rRNA. Its transition state resembles a fully dissociated ribooxacarbenium ion. A transition state analogue for ricin A-chain mimics the fully dissociated purine and cationic ribosyl transition state. The transition state for human purine nucleoside phosphorylase (PNP) is more dissociated than for the bovine enzyme. Immucillin-H, a powerful transition state inhibitor for human PNP, has entered clinical trials as an anti T-cell agent.
D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009696:Nucleic Acids / Q000378:metabolism*; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012276:Ricin / Q000378:metabolism
D004791:Enzyme Inhibitors; D004798:Enzymes; D009696:Nucleic Acids; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; D012276:Ricin; D011683:Purine-Nucleoside Phosphorylase