This research project involved three interrelated and interacting programs which bear on cardiac function and the enzymes which sustain it. The investigators involved with this project share a common interest in the structure; function relations of membrane-bound enzymes, electron transport processes, flavoprotein assembly and function, and the mechanism of action of inhibitors of these enzymes. The investigations are focussed on certain key enzyme which are known to play important roles in the metabolic processes of the mitochondrion and are important for energy generation by heart tissue. Enzymes such succinate dehydrogenase and its variant fumarate reductase are being studied along with p-cresol methylhydroxylase which is an excellent model for the biosynthesis of flavoproteins and the insertion of covalently bound flavin - an essential component of th other two enzyme above. Bacterial systems are used for some of the studies since they are simpler and can easily be manipulated and have been shown to exhibit most of the properties of their mammalian counterparts. Succinate dehydrogenase constitutes the only direct link between electron flow in the respiratory chain and the flux of carbon fragments in the TCA cycle. It has a role that is central to energy conservation by the cell. A deficiency in succinate dehydrogenase has been found in certain human mitochondrial myopathies and in heart attack patients. The experimental procedures used to study all of these enzyme of structure, to protein purification, an to genetic manipulation and kinetic analysis of the resultant altered proteins. Health relations, as noted above, include but are not limited to, cardiac myopathies.
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