Oxidation of fatty acids

Fatty acids obtained by hydrolysis of fats undergo different oxidative pathways designated as (a), beta (P) and omega (co) pathways. 

In 1904, Franz Knoop made a critical contribution to the elucidation of the mechanism of fatty acid oxidation and demonstrated that most of the fatty acids are degraded by oxidation at the p-carbon. p-Oxidation of fatty acids takes place in mitochondria. Fatty acids are activated before they enter into mitochondria for oxidation. 

Free fatty acids are introduced into the cytosol, but -oxidation occurs in the mitosol. Two situations occur. 

Note that two ATP equivalents are required the phosphoanhydride and thioester bonds are of similar free energies, so a second phosphoanhydride bond is also hydrolyzed to drive the reaction to completion. 

Carnitine Carrier The resulting acyl CoA ester is still not permeable to the mitochondrial membrane so a carrier system is needed. In this system the fatty acyl group is transferred from CoA-S to carnitine, diffuses across the membrane, and then transferred back to another CoA-S within the matrix  

Oxidation of fatty acids occurs in three well-defined steps namely, activation, transport into mitochondria, and oxidation to acetyl-CoA. 

In general, the entry of a fatty acid into a metabolic pathway is preceded by its conversion to its coenzyme A (CoASH) derivative this acyl derivative is called an alkanoyl- or alkenoyl-CoA, and in this form the fatty acid is said to have been activated. 

The activation of a fatty acid induces the formation of a thioester of fatty acid and CoA. The process is coupled to the hydrolysis of ATP to AMP. For palmitic acid, the reaction is  

The enzyme that catalyzes the reaction is acyl-CoA synthetase. 

Fatty acids of widely differing chain length can be activated, there being three acyl-CoA synthetase enzymes. One activates acetate (C2), propionate (C3), and butyrate (C4) a second activates medium-chain-length fatty acids (C4-CJ2) a third activates long- and medium-chain-length fatty acids. The long-chain acyl-CoA synthetase occurs in the mitochondria and endoplasmic reticulum and is widespread in mammalian tissues. 

Oxidation of higher fatty acids was first studied in 1904 by Knoop who fed animals with phenyl-substituted fatty acids and analyzed the products in the urine. He showed that the fatty acid oxidation results in the successive cleavage of two carbon moieties from the carboxyl end. Knoop coined the fatty acid oxidation mechanism as n-oxidation. As has been established by Kennedy and Lehninger in 1948-1949, oxidation of fatty acids occurs in the mitochondria only. Lynen and coworkers 

The fatty acids, as produced by intracellular hydrolysis of triacylglycerides or supplied to the cell from the blood, must be brought into a state of activation. Their activation is effected in the cytoplasm with the participation of acyl-CoA synthetase according to the scheme  

Since the activation process is effected extramitochondrially, transport of acyls across the membrane into the mitochondria is necessary. 

The transport is accomplished with the participation of carnitine, which takes up the acyl from acyl-CoA on the outer membrane side. Acylcamitine assisted by carnitine translocase diffuses to the inner side of the membrane to give its acyl to the CoA located in the matrix. The process of reversible acyl transfer between CoA and carnitine on the outer and inner sides of the membrane is effected by the enzyme acyl-CoA-camitine transferase. 

The oxidation of fatty acids within the Knoop-Lynen cycle occurs in the matrix. The Knoop-Lynen cycle includes four enzymes that act successively on acetyl-CoA. These are acyl-CoA dehydrogenase (FAD-dependent enzyme), enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (NAD-dependent enzyme), and acetyl-CoA acyltrans-ferase. Each turn, or revolution, of the fatty acid spiral produces 

The sequence continues with hydration, addition of water, to produce malate, which contains an oxidizable CHOH group. Oxidation involves NAD+, 

This sequence of reactions, namely oxidation of CH2-CH2 to CH=CH, then hydration to CH2-CHOH, followed by oxidation to CH2-CO, is a sequence we shall meet again in the -oxidation of fatty acids (see Section 15.4.1). The first oxidation utilizes FAD as coenzyme, the second NAD+. In both cases, participation of the oxidative phosphorylation system allows regeneration of the oxidized coenzyme and the subsequent generation of energy in the form of ATP. 

By combining the glycolytic pathway, the Krebs cycle, and oxidative phosphorylation, the energy yield from the aerobic degradation of glucose will be 

The total yield of 38 mol ATP by aerobic degradation of glucose may not be achieved under all circumstances, but it is, nevertheless, considerably more efficient than that from the anaerobic breakdown, namely 2 mol ATP (see Section 15.2). 

Fat degradation provides a major source of energy for most organisms. Fats are esters of glycerol with long-chain fatty acids (see Box 7.16) and are hydrolysed 

LEARNING GOAL Describe electron transport and the pro- 18.50 cess of oxidative phosphorylation calculate the ATP from the 18.51 complete oxidation of glucose. 

41 What reduced coenzymes provide the electrons for electron transport  

1842 What happens to the energy level as electrons are passed along in electron transport  

49 According to the chemiosmotic theory, how does the H gradient provide energy to synthesize ATP  

How are glycolysis and the citric acid cycle linked to the production of ATP by electron transport  

---

HisN03,(CH3)3N + -CH2 CH0H CH2C00-. Isolated from skeletal muscle. It acts as a carrier for ethanoyl groups and fatty acyl groups across the mitochondrial membrane during the biosynthesis or oxidation of fatty acids. 

Glyoxylate cycle A modification of the Krebs cycle, which occurs in some bacteria. Acetyl coenzyme A is generated directly from oxidation of fatty acids or other lipid compounds. 

The TCA cycle can now be completed by converting succinate to oxaloacetate. This latter process represents a net oxidation. The TCA cycle breaks it down into (consecutively) an oxidation step, a hydration reaction, and a second oxidation step. The oxidation steps are accompanied by the reduction of an [FAD] and an NAD. The reduced coenzymes, [FADHg] and NADH, subsequently provide reducing power in the electron transport chain. (We see in Chapter 24 that virtually the same chemical strategy is used in /3-oxidation of fatty acids.)... 

Mobilization of Fats from Dietary Intake and Adipo.se Ti.ssne /3-Oxidation of Fatty Acids /3-Oxidation of Odd-Carbon Fatty Acids /3-Oxidation of Unsatnrated Fatty Acids Other Aspects of Fatty Acid Oxidation... 

Several additional points should be made. First, although oxygen esters usually have lower group-transfer potentials than thiol esters, the O—acyl bonds in acylcarnitines have high group-transfer potentials, and the transesterification reactions mediated by the acyl transferases have equilibrium constants close to 1. Second, note that eukaryotic cells maintain separate pools of CoA in the mitochondria and in the cytosol. The cytosolic pool is utilized principally in fatty acid biosynthesis (Chapter 25), and the mitochondrial pool is important in the oxidation of fatty acids and pyruvate, as well as some amino acids. 

FIGURE 25.12 Elongation of fatty acids in mitochondria is initiated by the thiolase reaction. The /3-ketoacyl intermediate thus formed undergoes the same three reactions (in reverse order) that are the basis of /3-oxidation of fatty acids. Reduction of the /3-keto group is followed by dehydration to form a double bond. Reduction of the double bond yields a fatty acyl-CoA that is elongated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. 

Schulz, H. (1985). Oxidation of fatty acids. In Biochemistry of Lipids and Membranes (Vance, D.E. 

Mortensen PB. C6-C10-dicarboxyUc aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-cbain triacylglycerol. An in vivo measure of the rate of beta-oxidation of fatty acids. Biochim BiophysActa, 1981, 664(2), 349-355. 

The central role of the mitochondrion is immediately apparent, since it acts as the focus of carbohydrate, hpid, and amino acid metabohsm. It contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and ketogenesis, as well as the respiratory chain and ATP synthase. 

The onward metabohsm of succinate, leading to the regeneration of oxaloacetate, is the same sequence of chemical reactions as occurs in the P-oxidation of fatty acids dehydrogenation to form a carbon-carbon double bond, addition of water to form a hydroxyl group, and a hirther dehydrogenation to yield the oxo- group of oxaloacetate. 

Figure 22-3. 3-Oxidation of fatty acids. Long-chain acyl-CoA is cycled through reactions 2-5, acetyl-CoA being split off, each cycle, by thiolase (reaction 5). When the acyl radical is only four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5.

Oxidation of Fatty Acids Produces a Large Quantity of ATP... 

Impaired Oxidation of Fatty Acids Gives Rise to Diseases Often Associated With Hypoglycemia... 

Wood PA Defects in mitochondrial beta-oxidation of fatty acids. CurrOpin Lipidol 1999 10 107. 

Two major types of muscle fibers are found in humans white (anaerobic) and red (aerobic). The former are particularly used in sprints and the latter in prolonged aerobic exercise. During a sprint, muscle uses creatine phosphate and glycolysis as energy sources in the marathon, oxidation of fatty acids is of major importance during the later phases. Nonmuscle cells perform various types of mechanical work carried out by the structures constituting the cytoskeleton. These strucmres include actin filaments (microfilaments), micrombules (composed primarily of a- mbulin and p-mbulin), and intermediate filaments. The latter include keratins, vimentin-like proteins, neurofilaments, and lamins. 

The mechanisms of the metabolism and excretion of P-carotene are not clear, other than the identification of a number of partially oxidised intermediates found in plasma (Khachik et al., 1992). It is assumed that the carotenoids are metabolised in a manner analogous to the P-oxidation of fatty acids although there is no evidence for this. 

---