Saturated fatty acids oxidation

Consider the oxidation of palmitoleate. This Cjg unsaturated fatty acid, which has one double bond between C-9 and C-10, is activated and transported across the inner mitochondrial membrane in the same way as saturated fatty acids. Palmitoleoyl CoA then undergoes three cycles of degradation, which are carried out by the same enzymes as in the oxidation of saturated fatty acids. However, the cis-A 3-enoyl CoA formed in the third round is not a substrate for acyl CoA dehydrogenase. The presence of a double bond between C-3 and C-4 prevents the formation of another double bond between C-2 and C-3. This impasse is resolved by a new reaction that shifts the position and configuration of the cis-A double bond. An isomerase converts this double bond into a trans- A double bond. The subsequent reactions are those of the saturated fatty acid oxidation pathway, in which the trans- A 2-enoyl CoA is a regular substrate. 

See also Acetyl-CoA, Fats, Albumin, Fatty Acid Activation, Oxidation of Saturated Fatty Acids, Oxidation of Unsaturated Fatty Acids, Fatty Acid Biosynthesis Strategy, Palmitate Synthesis from Acetyl-CoA, Fatty Acid Desaturation, Essential Fatty Acids, Control of Fatty Acid Synthesis, Molecular Structures and Properties of Lipids (from Chapter 10)... 

See also Oxidation of Saturated Fatty Acids, Oxidation of Unsaturated Fatty Acids, Oxidation of Odd-Numbered Fatty Acids, Peroxisomal... 

For saturated fatty acids, the process of /3-oxidation involves a recurring cycle of four steps, as shown in Figure 24.10. The overall strategy in the first three steps is to create a carbonyl group on the /3-carbon by oxidizing the C, —C bond to form an olefin, with subsequent hydration and oxidation. In essence, this cycle is directly analogous to the sequence of reactions converting succi-... 

FIGURE 24.10 The /3-oxidation of saturated fatty acids involves a cycle of fonr enzyme-catalyzed reactions. Each cycle produces single molecnles of FADH, NADH, and acetyl-CoA and yields a fatty acid shortened by two carbons. (The delta [A] symbol connotes a double bond, and its superscript indicates the lower-nnmbered carbon involved.)... 

The next three steps—reduction of the /3-carbonyl group to form a /3-alcohol, followed by dehydration and reduction to saturate the chain (Figure 25.7) — look very similar to the fatty acid degradation pathway in reverse. However, there are two crucial differences between fatty acid biosynthesis and fatty acid oxidation (besides the fact that different enzymes are involved) First, the alcohol formed in the first step has the D configuration rather than the L form seen in catabolism, and, second, the reducing coenzyme is NADPH, although NAD and FAD are the oxidants in the catabolic pathway. 

The specific behaviour of unsaturated fatty acids under oxidation is determined by the position and the number of double bonds in the fatty acid molecule. The stepwise oxidation of an unsaturated acid to the position of a double bond in it proceeds in a manner similar to that of saturated acid oxidation. If the double bond retains the same configuration (trans-configuration) and position (A2,3) as those of the enoyl-CoA, which is produced during the oxidation of saturated fatty acids, the subsequent oxidation proceeds via conventional route. Otherwise, the oxidation reaction proceeds with the involvement of an accessory enzyme, A3,4-CiS-A2,3jrans-enoyl-CoA isomerase this facilitates the translocation of the double bond to an appropriate position and alters the double-bond configuration from cis to trans. 

The unsaturated fatty acid oxidation proceeds at a rate higher over that for saturated acids. For example, if the oxidation rate for saturated stearic acid is taken as a reference value, the oxidation rate for oleic acid is i 1 times, linolic acid, 114 times, linolenic acid, 170 times, and arachidonic acid, nearly 200 times as high as that for stearic acid. 

A compounding ingredient that enables an accelerator to exercise its maximum effect. Inorganic activators are metallic oxides (such as zinc, lead and magnesium oxides) and organic activators are long-chain saturated fatty acids, e.g., stearic and oleic. 

Excessive dietary intake of cholesterol and saturated fatty acids leads to decreased hepatic clearance of LDL and deposition of LDL and oxidized LDL in peripheral tissues. 

Passi, S., Picardo, M., Deluca, A., et al. (1993). Saturated dicarboxylic-acids as products of unsaturated fatty-acid oxidation. Biochimica et Biophysica Acta 1168 190-198. 

These points can be better appreciated by comparing the complete oxidation of glucose with that of a typical saturated fatty acid, palmitate. 

Glycerol provides a minor source of energy, in that it can be modified readily to glyceraldehyde 3-phosphate, one of the intermediates in the glycolytic pathway. The fatty acids are metabolized by a process termed P-oxidation, which involves the sequential removal of two-carbon units via oxidation at the P-position. The process for saturated fatty acids will now be described. 

Unsaturated fatty acids usually contain a cis double bond at position 9 or 12—e.g., linoleic acid (18 2 9,12). As with saturated fatty acids, degradation in this case occurs via p-oxida-tion until the C-9-ds double bond is reached. Since enoyl-CoA hydratase only accepts substrates with trans double bonds, the corresponding enoyl-CoA is converted by an iso-merase from the ds-A, cis- A isomer into the trans-A, cis-A isomer [1]. Degradation by p-oxidation can now continue until a shortened trans-A, ds-A derivative occurs in the next cycle. This cannot be isomerized in the same way as before, and instead is reduced in an NADPH-dependent way to the trans-A compound [2]. After rearrangement by enoyl-CoA isomerase [1 ], degradation can finally be completed via normal p-oxidation. 

Figure 8-4. 3-Oxidation of palmitate. Oxidation of an even-numbered, saturated fatty acid involves repetitive cleavage at the (1 carbon of the acyl chain. Removal of two-carbon units occurs in a cycle of four steps initiated by one of the acyl CoA dehydrogenases. Acetyl CoA is produced at each cycle until all that remains of the acyl CoA is acetyl CoA itself.

Because they contain fewer electrons within their structures, unsaturated fatty acids yield less energy than corresponding saturated fatty acids in P Oxidation. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

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 j8-oxidative processes as they occur in organelles other than mitochondria, and, finally, two less-general modes of fatty acid catabolism, a oxidation and [Pg.637]

The p Oxidation of Saturated Fatty Acids Has Four Basic Steps... 

The fatty acid oxidation sequence just described is typical when the incoming fatty acid is saturated (that is, has only single bonds in its carbon chain). However,... 

The major pathway for catabolism of saturated fatty acids is a mitochondrial pathway called (3-oxidation, in which two-carbon frag ments are successively removed from the carboxyl end of the fatly acyl CoA, producing acetyl CoA, NADH, and FADH2. 

Energy yield from fatty acid oxidation The energy yield from ihe P-oxidation pathway is high. For example, the oxidation of a molecule of palmitoyl CoA to C02 and H20 yields 131 AIRs (Figure 16.19). A comparison of the processes of synthesis and degradation of saturated fatty acids with an even number of car bon atoms is provided in Figure 16.20. 

Oxidation of fatty acids with an odd number of carbons The (3-oxidation of a saturated fatty acid with an odd number of carbon atoms proceeds by the same reaction steps as that of fatty acids with an even number, until the final three carbons are reached. This com pound, propionyl CoA, is metabolized by a three-step pathway (Figure 16.21). [Note Propionyl CoA is also produced during the metabolism of certain amino acids (see Figure 20.10, p. 264).]... 

Unsaturated fatty acids, such as Ci2H220 react with hydrogen gas, H2, to form saturated fatty acids, such as C12H2402. Are the unsaturated fatty acids being oxidized or reduced through this process ... 

Figure 17-12 The reactions of cytoplasmic biosynthesis of saturated fatty acids. Compare with pathway of (3 oxidation (Fig. 17-1).

The synthesis of fatty acids two carbon atoms at a time from acetyl-CoA has been considered in Chapter 17 and is outlined in Fig. 17-12. In this pathway, which resembles the P oxidation sequence in reverse, the products are saturated fatty acids with an even number of carbon atoms as shown in Fig. 21-2. In this section, we will consider some of the factors that lead to variations in the chain lengths and types of fatty acids. 

Fatty Acid Oxidation Yields Large Amounts of ATP Additional Enzymes Are Required for Oxidation of Unsaturated Fatty Acids in Mitochondria Ketone Bodies Formed in the Liver Are Used for Energy in Other Tissues Summary of Fatty Acid Degradation Biosynthesis of Saturated Fatty Acids... 

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