The specific aims of this proposal are (1) to develop the high- resolution NMR spectroscopy of living systems by modifying an existing spectrometer to image and record chemical shift data for the nuclei 3H and 13C; (2) to study metabolism in bacterial, fungal, plant and mammalian cells; (3) to gain insight, via the use of high-field NMR, into the mechanism of the biosynthesis and mode of action of vitamin B12, penicillin and related molecules which are of vital importance in health and disease; and (4) to use the highest resolving power of the NMR experiment to study the dynamics of enzyme mechanism at the molecular level, using cryoenzymology. The first long-term objective is to develop diagnostic and analytical NMR methods which will have general application for fingerprinting both normal and aberrant metabolic profiles in living systems, tissue, perfused organs and plasma, The second long-term objective is concerned with the development of NMR techniques, in combination with organic syntheses, enzymology and knowledge of crystal structures (where possible), to study mechanism at the molecular level in order to devise new mechanism-based inhibitors whose structures will provide a lead for the design of novel drugs to be used in the treatment of bacterial and parasitic infections, emphysema, etc.
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