β-Oxidation reactions: The first cycle of β-oxidation is shown in Figure 16.17. It consists of a sequence of four reactions involving the β-carbon (carbon 3) that results in shortening the fatty acid by two carbons at the carboxylate end. The steps include an oxidation that produces FADH2, a hydration, a second oxidation that produces NADH, and a CoAdependent thiolytic cleavage that releases a molecule of acetyl CoA. Each step is catalyzed by enzymes with chain-length specificity. [Note: For LCFA, the last three steps are catalyzed by a trifunctional protein.] These four steps are repeated for saturated fatty acids of even-numbered carbon chains (n/2) − 1 times (where n is the number of carbons), each cycle producing one acetyl CoA plus one NADH and one FADH2. The final cycle produces two acetyl CoA. The acetyl CoA can be oxidized or used in hepatic ketogenesis (see V. below). The reduced coenzymes are oxidized by the electron transport chain, NADH by Complex I, and FADH2 by coenzyme Q (see p. 75). [Note: Acetyl CoA is a positive allosteric effector of pyruvate carboxylase (see p. 119), thus linking fatty acid oxidation and gluconeogenesis.] 4. β-Oxidation energy yield: The energy yield from fatty acid β-oxidation is high. For example, the oxidation of a molecule of palmitoyl CoA to CO2 and H2O produces 8 acetyl CoA, 7 NADH, and 7 FADH2, from which 131 ATP can be generated. However, activation of the fatty acid requires two ATP. Therefore, the net yield from palmitate is 129 ATP (Fig. 16.18). A comparison of the processes of synthesis and degradation of long-chain saturated fatty acids with an even number of carbon atoms is provided in Figure 16.19.
adenine dinucleotide; NADH = nicotinamide adenine dinucleotide; TCA = tricarboxylic acid; CoQ = coenzyme Q; CO2 = carbon dioxide.
5.
Medium-chain fatty acyl CoA dehydrogenase deficiency: In mitochondria, there are four fatty acyl CoA dehydrogenase species, each with distinct but overlapping specificity for either short-, medium-, long-, or very-long-chain fatty acids. Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency, an autosomal-recessive disorder, is the most common inborn error of β-oxidation, being found in 1:14,000 births worldwide, with a higher incidence in Caucasians of Northern European descent. It results in decreased ability to oxidize fatty acids with six to ten carbons (which accumulate and can be measured in urine), severe hypoglycemia (because the tissues must increase their reliance on glucose), and hypoketonemia (because of decreased production of acetyl CoA; see p. 195). Treatment includes avoidance of fasting.
6.
Oxidation of fatty acids with an odd number of carbons: This process proceeds by the same reaction steps as that of fatty acids with an even number of carbons, until the final three carbons are reached. This product, propionyl CoA, is metabolized by a three-step pathway (Fig.
16.20). [Note: Propionyl CoA is also produced during the metabolism of certain amino acids (see Fig. 20.11, p. 266).] a.