Mitochondrial Beta-Oxidation of Medium Chain Saturated Fatty Acids

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation.
In order for beta-oxidation to begin, fatty acids are first activated by an acyl-coenzyme A synthetase, which uses ATP to produce a reactive fatty acyl adenylate that further reacts with coenzyme A to create a fatty acyl-CoA. There are different acyl-coenzyme A synthetases for the different lengths of fatty acids. Short and medium chain fatty acids are capable of diffusing directly into the mitochondria and are then activated by acyl-coenzyme A synthetases in the mitochondrial matrix. Long and very long chain fatty acids are activated by acyl-coenzyme A synthetases on the mitochondrial outer membrane. Transport of long and very long fatty acids into the mitochondria then requires carnitine O-palmitoyltransferase I and II, which combines fatty acyl-CoAs with carnitine to form acylcarnitines. Acylcarnitines can then be transported into the mitochondria using the carnitine acylcarnitine translocase enzyme.
In the first step of the beta-oxidation cycle, a double bond between C-2 and C-3 is formed, producing a trans-Δ2-enoyl-CoA. This is catalyzed by acyl-CoA-dehydrogenases in the mitochondria, which have forms specific to the different lengths of fatty acids. In the second step, enoyl CoA hydratase hydrates the newly formed double bond between C-2 and C-3, producing an L-beta-hydroxyacyl CoA. Next, L-beta-hydroxyacyl CoA dehydrogenase converts the hydroxyl group into a keto group, producing a beta-ketoacyl CoA. In the fourth and final step, the enzyme beta-ketothiolase cleaves the β-ketoacyl CoA and inserts the thiol group of another CoA between C-2 and C-3, reducing the acyl-CoA by 2 carbons and generating acetyl-CoA. The final two steps also have enzymatic forms specific to short chain fatty acids. Additionally, there is a trifunctional protein complex with enzymatic activity capable of performing all of the final 3 steps (hydratase, dehydrogenase, thiolase) in medium to very long chain fatty acids. This four step cycle repeats, removing 2 carbons from the fatty acid each time until it becomes acetyl-CoA. Acetyl-CoA is necessary for the citric acid cycle, among other cellular processes.

References

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