Carnitine-acylcarnitine translocase deficiency
Aug. 24, 2022
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Long-chain fatty acids (C16-C20) are stored as triglycerides in fat tissue. When required, fatty acids are released by lipases and activated toward coenzyme A (CoA) in the cytosol by thiokinases. Complete oxidation is possible only in the mitochondrion, and as the inner mitochondrial membrane is permeable for short- and medium-chain fatty acids but not for long-chain fatty acids, these are transported across the mitochondrial membrane via the carnitine cycle. Acyl-CoA compounds are converted to acylcarnitines by carnitine palmitoyltransferase I (CPT1), actively transported across the membrane by a translocase, and trans-esterified to acyl-CoA by carnitine palmitoyltransferase II (CPT2) on the matrix membrane. Except in hepatocytes, carnitine is transported into the cell (and reabsorbed in the kidney) by a carnitine transporter. The beta-oxidation spiral shortens fatty acid-CoA esters by 2 carbon atoms (1 molecule acetyl-CoA) in subsequent cycles. Each turn is catalyzed by several chain-length-specific enzymes: FAD-dependent dehydrogenases (very long-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase (MCAD), or short-chain acyl-CoA dehydrogenase (SCAD)) and NAD+-dependent trifunctional enzyme complexes with hydratase, dehydrogenase (long-chain L-3-hydroxyacyl-CoA dehydrogenase, MCHAD, SCHAD), and ketothiolase activities. Even-chain fatty acids are oxidized to acetyl-CoA. Odd-chain fatty acids yield to propionyl-CoA, which enters the Krebs cycle. Hydrogen generated by the dehydrogenases is transferred to the respiratory chain, either via FAD-containing electron-transfer flavoprotein (ETF) and ETF-coenzyme Q-oxidoreductase (ETF-QO) onto coenzyme Q or via NADH+ and H+ onto complex I. Acetoacetyl-CoA serves as substrate for the hepatic synthesis of the ketone bodies acetoacetate, 3-hydroxybutyrate, and acetone, which are used by extrahepatic tissue (muscle, brain) as an energy source, particularly during fasting or insulin deficiency. (Contributed by Dr. Georg F. Hoffmann.)