Molecular mechanisms of fatty acid beta-oxidation enzyme catalysis.

Abstract

The -oxidation of fatty acids is an important metabolic process that takes place in various organisms ranging from E. coli to Homo sapiens. In animal cells there are different -oxidation systems in mitochondria and peroxisomes. Mitochondrial -oxidation of fatty acids provides a significant part of the energy in some organs. For example, free fatty acids are the preferred substrate for energy production in heart. On the other hand, the peroxisomal -oxidation system degrades very long-chain fatty acids and other uncommon carboxylic acids but does not provide useful energy.1 More complexity was found in plant cells where glyoxysomes—which correspond to peroxisomes—have a unique -oxidation system.2 Fungi possess peroxisomal bifunctional -oxidation enzymes employing D-specific substrates but not L-isomers. The stereochemical specificity of the latter enzymes is the opposite of that for the animal peroxisomal trifunctional enzyme. During prolonged fasting or long-lasting exercise, mitochondrial -oxidation supplies energy to various tissues, producing acetyl-CoA for liver ketogenesis to supply circulating ketone bodies as an important alternative fuel in extrahepatic tissues. In addition to the mitochondrial matrix -oxidation enzymes, a long-chain-specific -oxidation enzyme system with a very long-chain acyl-CoA dehydrogenase and a trifunctional oxidation complex has been discovered on the mitochondrial inner membrane.5 Although the fatty acid -oxidation spiral comprises only four reactions, understanding of the complexity of fatty acid degradation has dramatically increased in recent years due to the discovery of a variety of new -oxidation enzymes. This article will discuss the enzymes that catalyze the second and third steps of the -oxidation pathway, an area of recent and substantial progress.