This study is aimed at elucidating the regulation of fatty acid oxidation in heart and ultimately at providing an in-depth understanding of beta- oxidation in normal and diseased animals. We have advanced a hypothesis about the regulation of beta-oxidation in response to changes in the energy demand of heart muscle. To obtain necessary evidence in support of this hypothesis, the effect of the intramitochondrial acetyl-CoA/CoASH ratio and the NADH/NAD+ ration on the rate of beta-oxidation in heart mitochondria will be evaluated. This evaluation necessitates measurements of several nucleotides and if detectable, of fatty acid metabolites in the mitochondrial matrix in addition to determining the effect of the NAD+/NADH ratio on the activity of long-chain L-3-hydroxyacyl-CoA dehydrogenase which will be purified and characterized. The effect of hormones, specifically growth hormone, insulin and epinephrine, on the rate of fatty acid oxidation will be evaluated with myocytes and mitochondria isolated from rats after treatment with these hormones and with myocytes directly challenged with these hormones. The design and evaluation of specific inhibitor of the enzymes of fatty acid oxidation, especially of L-3- hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase, will be continued with the aim of using such inhibitors for assessing the control strength of several reactions of the pathway. The mitochondrial metabolism of valproic acid, an anticonvulsant drug, is being studied with the aim of elucidating the mechanism by which this compound inhibits beta-oxidation. The planned synthesis of a specific and irreversible inhibitor of peroxisomal thiolase would provide an excellent tool for the ongoing evaluation of the peroxisomal contribution to the total beta-oxidation capacity of liver and heart. A rational design of beta-oxidation inhibitors from heart and liver which will be purified and characterized. Finally, the organization of beta-oxidation enzymes in multienzyme complexes and the effect of such arrangement on which codes for the multienzyme complex of beta-oxidation, will be cloned and sequenced. Also, the suspected organization of beta- oxidation enzymes in mitochondria will be investigated.
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