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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL018089-18
Application #
3335546
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1978-07-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
18
Fiscal Year
1993
Total Cost
Indirect Cost
Name
City College of New York
Department
Type
Schools of Arts and Sciences
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Abbas, A S; Wu, G; Schulz, H (1998) Carnitine acetyltransferase is not a cytosolic enzyme in rat heart and therefore cannot function in the energy-linked regulation of cardiac fatty acid oxidation. J Mol Cell Cardiol 30:1305-9
Yao, K W; Schulz, H (1996) Intermediate channeling on the trifunctional beta-oxidation complex from pig heart mitochondria. J Biol Chem 271:17816-20
Nada, M A; Abdel-Aleem, S; Schulz, H (1995) On the rate-limiting step in the beta-oxidation of polyunsaturated fatty acids in the heart. Biochim Biophys Acta 1255:244-50
Mao, L F; Chu, C; Luo, M J et al. (1995) Mitochondrial beta-oxidation of 2-methyl fatty acids in rat liver. Arch Biochem Biophys 321:221-8
Luo, M J; Mao, L F; Schulz, H (1995) Short-chain 3-hydroxy-2-methylacyl-CoA dehydrogenase from rat liver: purification and characterization of a novel enzyme of isoleucine metabolism. Arch Biochem Biophys 321:214-20
Yang, S Y; He, X Y; Schulz, H (1995) Glutamate 139 of the large alpha-subunit is the catalytic base in the dehydration of both D- and L-3-hydroxyacyl-coenzyme A but not in the isomerization of delta 3, delta 2-enoyl-coenzyme A catalyzed by the multienzyme complex of fatty acid oxidation from Biochemistry 34:6441-7
Luo, M J; Smeland, T E; Shoukry, K et al. (1994) Delta 3,5, delta 2,4-dienoyl-CoA isomerase from rat liver mitochondria. Purification and characterization of a new enzyme involved in the beta-oxidation of unsaturated fatty acids. J Biol Chem 269:2384-8
Yang, S Y; He, X Y; Styles, J et al. (1994) Primary structure of the large subunit of trifunctional beta-oxidation complex from pig heart mitochondria. Biochem Biophys Res Commun 198:431-7
Yao, K W; Mao, L F; Luo, M J et al. (1994) The relationship between mitochondrial activation and toxicity of some substituted carboxylic acids. Chem Biol Interact 90:225-34
Mao, L F; Chu, C; Schulz, H (1994) Hepatic beta-oxidation of 3-phenylpropionic acid and the stereospecific dehydration of (R)- and (S)-3-hydroxy-3-phenylpropionyl-CoA by different enoyl-CoA hydratases. Biochemistry 33:3320-6

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