title: Enzymatic transition states, transition-state analogs, dynamics, thermodynamics, and lifetimes.
abstract: Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits (a) the design of transition-state analogs as powerful enzymatic inhibitors, (b) exploration of protein features linked to transition-state structure, (c) analysis of ensemble atomic motions involved in achieving the transition state, (d) transition-state lifetimes, and (e) separation of ground-state (Michaelis complexes) from transition-state effects. Transition-state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein's dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA. vern.schramm@einstein.yu.edu
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007554:Isotopes / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry; D011487:Protein Conformation; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes; D007554:Isotopes; D009705:Nucleosides