Mitochondrial β-oxidation of saturated fatty acids in humans.

Mitochondrial β-oxidation of fatty acids generates acetyl-coA, NADH and FADH. Acyl-coA synthetases catalyze the binding of fatty acids to coenzyme A to form fatty acyl-coA thioesters, the first step in the intracellular metabolism of fatty acids. l-carnitine system facilitates the transport of fatty acyl-coA esters across the mitochondrial membrane. Carnitine palmitoyltransferase-1 transfers acyl groups from coenzyme A to l-carnitine, forming acyl-carnitine esters at the outer mitochondrial membrane. Carnitine acyl-carnitine translocase exchanges acyl-carnitine esters that enter the mitochondria, by free l-carnitine. Carnitine palmitoyltransferase-2 converts acyl-carnitine esters back to acyl-coA esters at the inner mitochondrial membrane. The β-oxidation pathway of fatty acyl-coA esters includes four reactions. Fatty acyl-coA dehydrogenases catalyze the introduction of a double bond at the C2 position, producing 2-enoyl-coA esters and reducing equivalents that are transferred to the respiratory chain via electron transferring flavoprotein. Enoyl-coA hydratase catalyzes the hydration of the double bond to generate a 3-l-hydroxyacyl-coA derivative. 3-l-hydroxyacyl-coA dehydrogenase catalyzes the formation of a 3-ketoacyl-coA intermediate. Finally, 3-ketoacyl-coA thiolase catalyzes the cleavage of the chain, generating acetyl-coA and a fatty acyl-coA ester two carbons shorter. Mitochondrial trifunctional protein catalyzes the three last steps in the β-oxidation of long-chain and medium-chain fatty acyl-coA esters while individual enzymes catalyze the β-oxidation of short-chain fatty acyl-coA esters. Clinical phenotype of fatty acid oxidation disorders usually includes hypoketotic hypoglycemia triggered by fasting or infections, skeletal muscle weakness, cardiomyopathy, hepatopathy, and neurological manifestations. Accumulation of non-oxidized fatty acids promotes their conjugation with glycine and l-carnitine and alternate ways of oxidation, such as ω-oxidation.