Although acetyl-CoA is both an end point of fatty acid catabolism and the starting substrate for fatty acid synthesis, break down is not simply the reverse of the biosynthetic pathway, but an entirely separate process taking place in a different compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives, is catalyzed by separate enzymes, utilizes NAD+ and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen.

Fatty Acids Are Transported in the Blood as Free Fatty Acids

Free fatty acids (FFAs)—also called unesterified (UFA) or non-esterified (NEFA) fatty acids—are fatty acids that are in the unesterified state. In plasma, longer-chain FFA are combined with albumin, and in the cell they are attached to a fatty acid–binding protein, so that in fact they are never really “free.” Shorter-chain fatty acids are more water soluble and exist as the unionized acid or as a fatty acid anion.

Fatty Acids Are Activated Before Being Catabolized

 Fatty acids must first be converted to an active intermediate before they can be catabolized. This is the only step in the complete degradation of a fatty acid that requires energy from ATP. In the presence of ATP and coenzyme A, the enzyme acyl-CoA synthetase (thiokinase) catalyzes the conversion of a fatty acid (or FFA) to an “active fatty acid” or acyl-CoA, using one high-energy phosphate and forming AMP and PPi (Figure 1). The PPi is hydrolyzed by inorganic pyrophosphatase with the loss of a further high-energy phosphate, ensuring that the overall reaction goes to completion. Acyl-CoA synthetases are found on the outer membrane of mitochondria and also in the endoplasmic reticulum and peroxisomes.

Fig1. Role of carnitine in the transport of long-chain fatty acids through the inner mitochondrial membrane. Long chain acyl-CoA formed by acyl-CoA synthetase enters the intermembrane space. For transport across the inner membrane, acyl groups must be transferred from CoA to carnitine-by-carnitine palmitoyl transferase-I. The acylcarnitine formed is then carried into the matrix by a translocase enzyme in exchange for a free carnitine and acyl-CoA is reformed by carnitine palmitoyltransferase-II.

Long-Chain Fatty Acids Cross the Inner Mitochondrial Membrane as Carnitine Derivatives

Acyl-CoAs formed as described earlier enter the intermembrane space (see Figure 1), but are unable to cross the inner mitochondrial membrane into the matrix where fatty acid breakdown takes place. In the presence of carnitine (β-hydroxy γ-trimethylammonium butyrate), a compound widely distributed in the body and particularly abundant in muscle; however, carnitine palmitoyltransferase-I, an enzyme located in the outer mitochondrial membrane, transfers the long-chain acyl group from CoA to carnitine, forming acylcarnitine and releasing CoA. Acylcarnitine is able to penetrate the inner membrane and gain access to the β-oxidation system of enzymes via the inner membrane exchange transporter carnitine-acylcarnitine translocase. The transporter binds acylcarnitine and transports it across the membrane in exchange for carnitine. The acyl group is then transferred to CoA so that acyl-CoA is reformed and carnitine is liberated. This reaction is catalyzed by carnitine palmitoyltransferase-II, which is located on the inside of the inner membrane (see Figure 1).

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