Fatty acid, activation oxidation spiral

A major determinant of the mitochondrial fatty acid oxidation normally in liver is the delivery rate of activated fatty acyl groups to the enzymes of the P-oxidation spiral in the matrix. Although the importance of the delivery of free fatty acids to liver is well established in this regard, the fact that at times intracellular lipolysis alone can provide enough free fatty acids for oxidation needs to be appreciated. The observations that livers from diabetic rats continue to produce ketone bodies nearly maximally, even when perfused with medium lacking fatty acids, attests to the ability of intracellular lipolysis to furnish substrates for p-oxidation for appreciable periods, at least in liver, and to its activation in the diabetic state (Krebs et aL, 1969 Van Harken et aL, 1969) indirect evidences indicate that a cyclic AMP dependent hormone sensitive lipase exists in liver (for references, see Lund et aL, 1980). 

Dietary medium-chain-length fatty acids are more water soluble than long-chain fatty acids and are not stored in adipose triacylglyce. After a meal, they enter the blood and pass into the portal vein to the liver. In the liver, they enter the mitochondrial matrix by the monocarboxylate transporter and are activated to acyl CoA derivatives in the mitochondrial matrix (see Fig. 23.1). Medium-chain-length acyl CoAs, like long-chain acyl CoAs, are oxidized to acetyl CoA via the (3-oxidation spiral. Medium-chain acyl CoAs also can arise from the peroxisomal oxidation pathway. 

Within the liver, they bind to fatty acid-binding proteins and are then activated on the outer mitochondrial membrane, the peroxisomal membrane, and the smooth endoplasmic reticulum by fatty acyl CoA synthetases. The fatty acyl group is transferred from CoA to carnitine for transport through the inner mitochondrial membrane, where it is reconverted back into fatty acyl CoA and oxidized to acetyl CoA in the (3-oxidation spiral (see Chapter 23). 

If it arises from pyruvate (Topic 14), the formation of acetyl CoA is pushed by the energetically favourable oxidative decarboxylation reaction. If, on the other hand, one starts from acetate, or similarly from a long-chain fatty acid waiting to enter the fatty oxidation spiral, the formation of the acyl CoA involves an activation reaction in which ATP is split. 

Whereas the mitochondrial enzymes of p-oxidation reside within the area bound by inner membrane, activation of fatty acids proceeds largely at sites exterior to this membrane. The transport of activated acyl groups across the inner mitochondrial membrane Is brought about by a carnitine dependent route (Fritz, 1963 Bremer, 1968 Bressler, 1970). A carnitine acyltransferase localized on the outer aspect of inner membrane utilizes cytosolic free carnitine to convert the cytosolic acyl-CoA to cytosolic acylcarnitine (Fig. 1). A translocase of the inner membrane then moves the acylcarnitine inside in exchange for the simultaneous movement of carnitine in the opposite direction. Another carnitine acyltransferase, situated on the inner side of the inner membrane, utilizes matrix CoA to convert acylcarnitine to acyl-CoA, thus producing the latter in the same compartment where enzymes of the p-oxidation spiral exist (Pande, 1975 Ramsay and Tubbs, 1975 Tubbs and... 

Evidence so far indicates that substrate and cofactor availability, and product inhibition, constitute the main modes for the regulation of fatty acid oxidation within mitochondria there is nothing to indicate that substrate flow over the p-oxidation spiral is further regulated by allosteric or covalent modification of the activity of any enzyme of this spiral. As is to be expected for a multistep metabolic pathway, diverse steps contribute to the overall regulation of fatty acid oxidation in different tissues under different conditions. /S/lore is known about this process in liver and heart than in other tissues and its brief description follows. 

Fatty Acid Oxidation Spiral. The individual reactions of fatty acid oxidation require the activation of the fatty acid by formation of a thioester with CoA. Subsequent oxidation, dehydration, oxidation, and cleavage all occur only with the acyl CoA compounds (II). The product... 

---