Catalysis and reactivity in carnohydrate chemistry and biochemistry

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The research outlined in this proposal involves two main areas of carbohydrate (sugar) chemistry.  We plan to investigate the fundamental aspects of the biological reactions of carbohydrates and how they deviate from the corresponding reactions in water.  Organisms are complex entities whose very existence depends on the ability to metabolize various dietary nutrients.  Two distinct phases of metabolism exist: (1) energy-yielding catabolic processes that involve the degradation of complex food sources such as carbohydrates, proteins, and fats to produce simpler molecules; and (2) anabolism, that phase that is concerned with biosynthetic processes in which simple components, such as glucose are used to form more complex molecules that are required for the growth and survival of an organism.  These two types of metabolic pathways employ enzymes that are either specific for degradation-type reactions, or that function in reactions which lead to the assembly of complex molecules. A goal of this project is to design inhibitors for both types of sugar processing enzymes because many of these enzymes are implicated in various ailments including tuberculosis and Fabry's disease.  The inhibitors made during the course of this program of research will have the potential to become therapeutic agents.  A second goal of this proposal is to apply the fundamental information gained from the carbohydrate reaction mechanism studies to the modification of sugar-catabolizing enzyme (a glycosidase) so that it can degrade sugars using a novel mechanism of action.  What would be the advantage of modifying a glycosidase in this way?  Information gleaned from this study will allow researchers to get a better understanding of biological evolution and how nature slower, but inexorably, improves enzyme efficiency.