Understanding the integration of metabolic pathways will be one of the challenges for biologists in the post-genomics era. To meet this challenge, cell physiologists will rely on solid knowledge of the biochemistry underpinning the metabolic pathways in the cell. The study of major metabolic pathways like the one dedicated to the synthesis of adenosylcobalamin (coenzyme B12) offers an opportunity to reveal the strategies used by the cell to manufacture the most structurally complex coenzyme whose steady intracellular level is very low, and to learn how this major pathway is integrated with other metabolic processes in the cell. De novo synthesis of coenzyme B12 is performed only by procaryotes, but it is an essential nutrient for humans and animals in general. A diet devoid of cobalamin leads to a condition known as pernicious anemia. The inability of the human cell to convert the vitamin form to its coenzymic form results in severe health problems. Conversion of the vitamin to the coenzymic form requires the attachment of the upper ligand 5'-deoxyadenosine, and this reaction is catalyzed by an adenosyltransferase enzyme. One of the objectives of the proposed work is to further our understanding of how a bacterial adenosyltransferase enzyme works. This knowledge will serve as the foundation for future work on the human enzyme aimed at solving the problem of the lack or lower activity of this enzyme. We are also studying the enzyme that catalyzes a reaction critical to the use of precursors present in the environment and to de novo coenzyme B12 biosynthesis. A complete understanding of how this enzyme works will facilitate the design of drugs that could block its activity, thus preventing salvaging and de novo synthesis of coenzyme B12. Gaps of knowledge remain regarding many aspects of the coenzyme B12 biosynthetic pathway. We take a multifaceted approach to fill these gaps, and work together with structural biologists and chemists to bring our understanding of these processes to a level not afforded by single-discipline . approaches.
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