Abstract
In an attempt to clarify why the brain oxidizes fatty acids poorly or not at all, the activities of beta-oxidation enzymes present in rat brain and rat heart mitochondria were measured and compared with each other. Although the apparent Km values and chain-length specificities of the brain and heart enzymes are similar, the specific activities of all but one brain enzyme are between 4 and 50% of those observed in heart mitochondria. The exception is 3-ketoacyl-CoA thiolase (EC 2.3.1.16) whose specific activity in brain mitochondria is 125 times lower than in heart mitochondria. The partially purified brain 3-ketoacyl-CoA thiolase was shown to be catalytically and immunologically identical with the heart enzyme. The low rate of fatty acid oxidation in brain mitochondria, estimated on the basis of palmitoylcarnitine-supported respiration and [1-14C]palmitoylcarnitine degradation to be less than 0.5 nmol/min/mg of protein, may be the consequence of the low activity of 3-ketoacyl-CoA thiolase. Inhibition of [1-14C]palmitoylcarnitine oxidation by 4-bromocrotonic acid proves the observed oxidation of fatty acids in brain to be dependent on 3-ketoacyl-CoA thiolase and thus to occur via beta-oxidation. Since the reactions catalyzed by carnitine palmitoyltransferase (EC 2.3.1.21) and acyl-CoA synthetase (EC 6.2.1.3) do not seem to restrict fatty acid oxidation in brain, it is concluded that the oxidation of fatty acids in rat brain is limited by the activity of the mitochondrial 3-keto-acyl-CoA thiolase.
Highlights
In an attemptto clarify why the brainoxidizes fatty unable to oxidize fatty acids due to their exclusion by the acids poorly or not atall, the activities of @-oxidation blood-brain barrier [6,7]
Specific Activities of @-OxidcrtionEnzymes inRat Brain and Rat Heart Mitochondria-In an attempt toestablish whether any single @-oxidationenzyme is responsible for the limited capacity of brain mitochondria to oxidize fatty acids, we determined the specific activities of these enzymes inrat brain and rat heart mitochondria and compared them with each other
Forexample, evidence suggests that theratelimiting step in heart is catalyzed by 3-ketoacyl-CoAthiolase whose activity can be modulated by the acetyl-CoA/CoASH ratio[30].In liver, fatty acid oxidation isbelieved to be controlled via the regulation of carnitine palmitoyltransferase I [31] which catalyzes the rate-limiting step or one of the slow steps of the pathway
Summary
[l-14C]palmitoylcarnitinedegradation to be less than 2-decenoic acid were obtained from Aldrich. 0.5 nmol/min/mg of protein, may be the consequence of the low activity of 3-ketoacyl-CoA thiolase. The concentrations of CoA derivatives were determined acids in brain to be dependenont 3-ketoacyl-CoA thio- by the method of Ellman [16] after cleaving the thioester bond with lase and to occurvia @-oxidation.Since the reac- hydroxylamine at pH 7. Concluded that the oxidation foaftty acids in rat brain Palmitoyl-L-carnitine was generously provided by Dr K. Brendel, is limited by theactivity of the mitochondrial3-ketoacyl-CoA thiolase. A suspension of Staphylococcus aureus cells (Cowan strain), pig heart 3-hydroxyacyl-CoA dehydrogenase, Ficoll (type 400-DL), L-malate, ADP, and all other standard biochemicals were obtained from Sigma
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