REGULATION OF THIOLASES AND CONTROL OF FATTY ACID OXIDATION IN HEART.
Item
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Title
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REGULATION OF THIOLASES AND CONTROL OF FATTY ACID OXIDATION IN HEART.
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Identifier
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AAI8212207
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identifier
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8212207
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Creator
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OLOWE, YETUNDE OYINLOLA.
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Date
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1982
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry
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Abstract
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4-Bromocrotonic acid was found to effectively inhibit respiration supported by either palmitoylcarnitine or acetoacetate in coupled rat heart mitochondria. Partial inhibition was observed when 3-hydroxybutyrate served as a substrate, whereas pyruvate-supported respiration was unaffected by the inhibitor. Thus, 4-bromocrotonic acid inhibits fatty acid oxidation and ketone body degradation. When the enzymes of B oxidation and ketone body degradation were assayed in mitochondria preincubated with 4-bromocrotonic acid only 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase were found to be inactive. 4-Bromocrotonic acid was enzymatically converted to 3-keto-4-bromobutyryl-CoA which effectively inhibited both thiolases. A kinetic evaluation of the inhibitions caused by 4-bromocrotonic acid in coupled rat heart mitochondria demonstrated that 3-ketoacyl-CoA thiolase and respiration supported by palmitoylcarnitine are inactivated at equal rates. Acetoacetyl-CoA thiolase was however inactivated more rapidly than was respiration supported by acetoacetate suggesting that the thiolase-catalyzed step is rate-limiting in B oxidation. In contrast the thiolytic cleavage of acetoacetyl-CoA does not seem to be rate-limiting in ketone body degradation.;The effects of various mitochondrial coenzymes and metabolites on the activities of 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase from pig heart were investigated with the aim of elucidating possible regulation of these two enzymes. Of the compounds tested, acetyl-CoA was the most effective inhibitor of both thiolases. However, 3-ketoacyl-CoA thiolase was more severely inhibited by acetyl-CoA than was acetoacetyl-CoA thiolase. 3-ketoacyl-CoA was also significantly inhibited by decanoyl-CoA while acetoacetyl-CoA thiolase was inhibited by 3-hydroxybutyryl-CoA as strongly as it was by acetyl-CoA. All other compounds either did not affect the thiolase activities or only at unphysiologically high concentrations. The inhibition of acetoacetyl-CoA thiolase by acetyl-CoA was linear and apparently noncompetitive with respect to CoASH (K(,i) = 125uM) whereas that of 3-ketoacyl-CoA thiolase was nonlinear. However, at low concentrations of acetyl-CoA the inhibition of 3-ketoacyl-CoA thiolase was linear competitive with respect to CoA (K(,i) = 3.9uM). Consequently, 3-ketoacyl-CoA thiolase, but not acetoacetyl-CoA thiolase, will be completely inhibited by acetyl-CoA at concentrations of CoASH and acetyl-CoA which are assumed to exist intramitochondrially at state-4 respiration. It is suggested that fatty acid oxidation in heart muscle at sufficiently high concentrations of plasma free fatty acids may be controlled via the regulation of 3-ketoacyl-CoA thiolase by the acetyl-CoA/CoA ratio.;Thiolase does not seem to be regulated by phosphorylation.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biochemistry
