JS Oxidation, of fatty acids

The jS-oxidation of fatty acids involves the conversion of fatty acids to the acyl-CoA derivative, which is in turn reduced and converted to jS-hydroxyacyl CoA. After reduction to the jS-ketoacyl CoA by the hydroxyl CoA dehydrogenase, the acyl derivative is split in the presence of thiolase to yield acyl-CoA and an acyl derivative of the original fatty acid shorter by two carbons. When even-numbered fatty acids are oxidized, 4-carbon compounds, jS-hydroxybutyryl CoA, and acetoacyl CoA are formed. All the reactions of jS-oxidation of fatty acids are readily reversible, except for the thiolase reaction, the equilibrium of which lies in the direction of the cleavage. 

At the time that the glyoxysome particle was discovered, it was assumed that jS-oxidation of fatty acids was completed in the mitochondrion and the resultant acetyl CoA transported to the glyoxysome for conversion to succinate. But it was difficult to explain how this acetyl CoA avoided complete oxidation in the mitochondrion or even how it could be transferred from one organelle to another. The problem was resolved when it was shown that j5-oxidation also occurs in the glyoxysome and that the acetyl CoA is produced and consumed in the same organelle [44, 72]. 

Notice that reactions 6, 7, and 8 in the citric acid cycle are similar to reactions 1, 2, and 3 in the jS-oxidation of fatty acids (Section 25.6). 

A mechanism for the biodegradation of PE was presented in 1987 [5] and shows similarities with the typical jS-oxidation of fatty acids and paraffins in man and in animals. In the biodegradation of PE an initial abiotic step involves oxidation of the polymer chain. Once hydroperoxides are formed there is a gradual increase in the amount of keto-carbonyl groups in the polymer. 

Individuals with either type of diabetes are unable to take up glucose efficiently from the blood recall that insulin triggers the movement of GLUT4 glucose transporters to the plasma membrane of muscle and adipose tissue (see Fig. 12-8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by JS oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by JS oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and /3-hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to /3-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate ... 

Most fatty acids have an even number of carbon atoms, so that none are left Over after jS-oxidation. Those fatty acids with an odd number of carbon atoms or with double bonds require additional steps for degradation, but all carbon atoms are ultimately released for further oxidation in the citric acid cycle. 

Metabolic Role. Riboflavin coenzymes are required for most oxidations of carbon-carbon bonds (Fig. 8.29). Examples include the oxidation of succinyl CoA to fumarate in the Krebs cycle and introduction of a,jS-unsaturation in /3-oxidation of fatty acids. Riboflavin is also required for the metabolism of other vitamins, including the reduction of 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate (Fig. 8.49), and interconversion of pyridoxine-pyridoxal phos-phate-pyridoxamine (Fig. 8.33). Because oxi-dation/reductions that use FAD or FMN as the coenzyme constitute a two-step process, some flavin coenzyme systems contain more than one FAD or FMN. 

This transport is accomplished by carnitine (L-jS-hydroxy-y-trimethylammonium butyrate), which is required in catalytic amounts for the oxidation of fatty acids (Figure 18-1). Carnitine also participates in the transport of acetyl-CoA for cytosolic fatty acid synthesis. Two carnitine acyl-transferases are involved in acyl-CoA transport carnitine palmitoyltransferase I (CPTI), located on the outer surface of the inner mitochondrial membrane, and carnitine palmitoyltransferase II (CPTII), located on the inner surface. 

Alpha-oxidation of fatty acids has also been reported in plants, a process which involves sequential removal of one carbon at a time from free fatty acids of chain length ranging from C13 to Cig- It is unlikely that complete oxidation of fatty acids occurs in this manner, and the physiological significance of this pathway is obscure. It could well serve to shorten odd-chain fatty acids to even lengths and thus allow their degradation by jS-oxidation. 

As a rule, the anabolic pathway by which a substance is made is not the reverse of the catabolic pathway by which the same substance is degraded. The two paths must differ in some respects for both to be energetically favorable. Thus, the y3-oxidation pathway for converting fatty acids into acetyl CoA and the biosynthesis of fatty acids from acetyl CoA are related but are not exact opposites. Differences include the identity of the acvl-group carrier, the stereochemistry of the / -hydroxyacyl reaction intermediate, and the identity of the redox coenzyme. FAD is used to introduce a double bond in jS-oxidalion, while NADPH is used to reduce the double bond in fatty-acid biosynthesis. 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

We now take a closer look at the first stage of fatty acid oxidation, beginning with the simple case of a saturated fatty acyl chain with an even number of carbons, then turning to the slightly more complicated cases of unsaturated and odd-number chains. We also consider the regulation of fatty acid oxidation, the jS-oxidative processes as they occur in organelles other than mitochondria, and, finally, two less-general modes of fatty acid catabolism, a oxidation and w oxidation. 

Acetoacetyl CoA could be the stump of the successive jS-oxidation of even-numbered fatty acids, or it could result from the condensation of two molecules of acetyl CoA. In the last step of even-numbered, straight-chain fatty acid oxidation, the split involves a reaction between the acetoacetic enzyme complex and reduced CoA. The product of the reaction is acetyl CoA and a complex between the enzyme and acetic acid. 

Further jS-oxidation of 6-OH 12-1 (2 trans) would yield 2-OH 8 0, which cannot then be oxidized. To circumvent this the hydrogen is removed from the hydroxyl to yield an oxygenated (or oxo) derivative, which is converted to the 7 0 fatty acid by a-oxidation. 

Comparison of the illustrated pathway to 3.5) (Scheme 3.2 cf. Scheme 3.4) with that of fatty acid biosynthesis (Section 1.1.2 Scheme 1.2) indicates that a clear distinction between them is achieved by the absence of a reductase in polyketide formation, i.e. oxygen atoms of acetate are retained in polyketide metabolites. In the case of orsellinic acid 3.4), in particular, results of experiments with [ Ojacetate established this to be correct [10]. It should be noted, however, that universal retention of acetate oxygen through the poly-jS-keto-acyl-CoA to the final metabolite is not observed. One is missing, for example, in 6-methylsalicyclic acid 3.14) and several in curvularin 3.87). (See, especially. Section 3.9 for what appear to be polyketides formed with varying levels of oxidation and dehydration corresponding to the steps illustrated in Scheme 1.2, Section 1.1.2.)... 

With respect to the enzymes involved in the jS-oxidation of all these compounds, it was long thought that only a single set of enzymes including acyl-CoA oxidase, L-bifunctional protein with enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity and peroxisomal thiolase would catalyze the -oxidation of all these compounds. It now turns out, however, that peroxisomes harbor two acyl-CoA oxidases, one for straight-chain fatty acids like C26 0 and one for branched-chain fatty acids (pristanic acid, DHCA and THCA), two bifunctional enzymes and two peroxisomal thio-lases (see Fig. 25.2). This will be discussed in more detail under paragraph 25.2. 

It was found by all workers in this field that acetyl-CoA acted as a primer of the synthetic process and became incorporated into the tail end of the fatty acid, which thus is formed by the successive addition of Cg-units derived from malonyl-CoA to the primer acetyl-CoA. In this function acetyl-CoA could be replaced by a great variety of saturated straight or branched chain acyl-CoA. In contrast, the oxidized intermediate compounds which occur in the course of fatty acid degradation, such as a,jS-unsaturated-,... 

Ketoacyl-CoA thiolase catalyzes the cleavage of a jS-ketoacyl-CoA to give acetyl CoA, the final step in the jS-oxidation cycle of fatty-acid metabolism. 

In 1957 Seubert, Greull, and Lynen used partially purified mitochondrial enzymes of jS-oxidation to synthesize fatty acids of medium chain length. The successful reversal of fatty acid oxidation required Langdon s (1955) reducing enz)une (NADPH-enoyl-GoA oxidoreduc-tase) which is present in mitochondria and microsomes but is not... 

L-Carnitine (4-trimethylamino-3-hydroxybutyric acid) is necessary for the mitochondrial jS-oxidation of long-chain fatty acids which are converted from their acyl-CoA esters into the corresponding carnitine esters for transport through the inner mitochondrial membrane. Thus in carnitine deficiency, jS-oxidation of long-chain fatty acids becomes impaired, leading to their... 

Long-chain odd-number fatty acids are oxidized in the same pathway as the even-number acids, beginning at the carboxyl end of the chain. However, the substrate for the last pass through the jS-oxidation sequence is a fatty acyl-CoA with a five-carbon fatty acid. When this is oxidized and cleaved, the products are acetyl-CoAand propionyl-CoA. The acetyl-CoA can be oxidized in the citric acid cycle, of course, but propionyl-CoA enters a different pathway involving three enzymes. 

Answer Malonyl-CoA would no longer inhibit fatty acid entry into the mitochondrion and jS oxidation, so there might be a futile cycle of simultaneous fatty acid synthesis in the cytosol and fatty acid breakdown in mitochondria. (See Fig. 17-12.)... 

Step 1 of Figure 29.3 Introduction of a Double Bond The /3-oxidation pathway begins when a fatty acid forms a thioester with coenzyme A to give a fatty acyl Co . Two hydrogen atoms are then removed from C2 and C3 of the fatt) acyl Co.A by one of a family of acyd-CoA dehydrogena.s es to yield an conjugated double bond into a carbonyl compound—occurs froc uently in biochemical pathways and usually involves the coenzyme flavin adenine dinucleotide (FAD). Reduced FADI-I2 is the by-product. 

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