Several projects are proposed to further the ability of researchers to determine the transition-state structure of bioorganic reactions. The biomedical significance of the research is the improvements it offers in understanding the fundamental principles underlying efforts in rational drug design. Many disease processes are the result of an enzyme functioning out of control. The enzymes are controlled using drugs that act as inhibitors of the enzyme. Antipathogenic agents are also often specific inhibitors of key metabolic enzymes of a particular pathogen. Understanding transition-state structure is central to the rational design of medicines that act as enzyme inhibitors.
The specific aims of the project are: 1. To define the role that hydrogen bonds play in determining the reactivity of bases in model reactions for enzymes. Solvent isotope effects, substrate isotope effects, and isotope effects on isotope effect will be used to study the extent of base desolvation in the transition state for a proton transfer from a carbon acid. The degree to which solvent motions around the base are coupled to the proton transfer event will also be determined. 2. To develop methods for calculating isotopic fractionation factors of strong hydrogen bonds thought to be important in enzymic catalysis. Several researchers have proposed recently new theories about he origins of enzymic catalytic power. The stabilizing effects of short, strong hydrogen bonds are thought to be central features of the mechanisms used by enzymes to reduce the barrier heights for chemical reactions. The present proposal is a plan to develop methods for model calculations which can be used to test and further refine theories of enzymic catalysis. 3. To use carbon isotope effects to determine transition state structures in enzymic decarboxylations. A new laser-based technique for high- precision measurements of isotope ratios will be developed and tested for use in studying the mechanisms of reactions catalyzed by enzymes.
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