4-Bromocrotonic acid, an effective inhibitor of fatty acid oxidation and ketone body degradation in rat heart mitochondria. On the rate-determining step of beta-oxidation and ketone body degradation in heart.
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 beta-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. Evidence is presented for the enzymatic conversion of 4-bromocrotonic acid to 3-keto-4-bromobutyryl-CoA which effectively inhibits 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 palmitoyl carnitine are inactivated at equal rates. However, acetoacetyl-CoA thiolase was inactivated more rapidly than was respiration supported by acetoacetate. It is suggested that the thiolase-catalyzed step is rate-limiting in beta-oxidation or is as slow as other reactions are. In contrast the thiolytic cleavage of acetoacetyl-CoA does not seem to be rate-limiting in ketone body degradation.
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism*; D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D003437:Crotonates / Q000494:pharmacology*; D004746:Enoyl-CoA Hydratase / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006836:Hydro-Lyases / Q000378:metabolism*; D007657:Ketone Bodies / Q000378:metabolism*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002087:Butyrates; D003437:Crotonates; D005227:Fatty Acids; D007657:Ketone Bodies; C034444:4-bromocrotonic acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D044943:Fatty Acid Desaturases; D000217:Acyltransferases; D000102:Acetyl-CoA C-Acyltransferase; D006836:Hydro-Lyases; D004746:Enoyl-CoA Hydratase