Fatty acids oxidative desaturation

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. 

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)... 

The metabolism of CLA in peroxisomes shows interesting aspects in terms of a possible role in the formation and concentration of eicosanoids, especially as effected in different pathologic conditions. By either competing with linoleic acid for desaturation and elongation, or via peroxisomal P-oxidation, CLA may interfere with eicosanoid production and degradation. It is likely however that its action may depend on its incorporation and thereby its concentration in different tissues. The different rate of peroxisomal P-oxidation between t 0,c 2 and c9,tll, may also explain the different biological activities of the two isomers. Also, enhanced fatty acid oxidation... 

The Incubation of the Isolated hepatocytes was performed at 25 C to minimize fatty acid oxidation without greatly affecting fatty acid desaturation and incorporation. 

Another possible explanation for the low R. Q. s obtained after high-fat diets over short periods by Hawley, Johnson and Murlin186 is that in the oxidation of fatty acid chains the uptake of oxygen may outrun the production of carbon dioxide and thus lower the R. Q. Such a process of desaturation would remove the hydrogen but would not produce any carbon dioxide. 

If a fatty acid already has a double bond in it, the scheme by which the fatty acid is oxidized depends on where the double bond ends up after several of the C-2 fragments have been removed by normal p oxidation. With a double bond already present, the enzyme that catalyzes the first step (insertion of the double bond at C-2) gets confused when there is already a double bond at C-2 or at C-3. The fact that the double bonds in unsaturated fatty acids are invariably cis also complicates life since the double bond introduced at C-2 by the desaturating enzyme of p oxidation is a trans double bond. 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

The FAS multi-enzyme complex synthesizes saturated C16 fatty acids, but cells and tissues need unsaturated and longer chain fatty acids. The palmitoyl-CoA can be modified by either chain elongation and/or oxidation in order to produce different fatty acid molecules. Both elongation and desaturation occur within the smooth endoplasmic reticulum (SER, microsomal fraction) of the cell. 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

A variety of unsaturated fatty acids can be formed from oleate by a combination of elongation and desaturation reactions. For example, oleate can be elongated to a 20 1 cis-A fatty acid. Alternatively, a second double bond can be inserted to yield an 18 2 cis-A, A fatty acid. Similarly, palmitate (16 0) can be oxidized to palmitoleate (16 1 cis-A ), which can then be elongated to cA-vaccenate (18 1 cis-A H). 

Intestinal Handling of FFA In the cells of the small intestine, several enzymes can act on free but not on esterified fatty acids. In contrast to MAGs, FFA are diluted with fatty acids originating from the plasma free fatty acid pool (44). After activation they can be oxidized, elongated, chain desaturated, and converted into complex lipids (45, 46). The relative rates depend on the nature of the fatty acids and on the presence of other components in the intestinal cells (47). Conversion of saturated fatty acids in monounsaturated ones when they are absorbed as FFA, i.e., when they were present in the outer position of the dietary TAGs, could... 

The effect different fatty acids have on cholesterolemia is well known. Whatever the kind of the effect (hyper- or hypocholesterolemic), it seems to be more pronounced when the fatty acids are esterified at the inner than at the outer positions of TAGs. The lower hypercholesterolemic effect of saturated fatty acids at the outer positions (64) can be the result of a combination of different factors such as reduced absorption by unabsorbable soap formation, which in turn interferes with cholesterol absorption in the intestinal lumen, partial desaturation and oxidation in the small intestinal cells, and reduced targeting into the fiver (63). The stronger hypocholesterolemic effect of polyunsamrated fatty acids at the i -2-position (65) could be the result of increased influx in the liver (66). 

A. Arachidonic acid is produced from linoleic acid (an essential fatty acid) by a series of elongation and desaturation reactions. Arachidonic acid is stored in membrane phospholipids, released, and oxidized by a cyclooxygenase (which is inhibited by aspirin) in the first step in the synthesis of prostaglandins, prostacyclins, and thromboxanes. Leukotrienes require a lipoxygenase, rather than a cyclooxygenase, for their synthesis from arachidonic acid. 

One molecule of oxygen accepts two pairs of electrons, one from palmitoyl-CoA and the other from NADPH or NADH. The electrons NAD(P)H are transported via cytochrome-bs reductase to cytochrome bs (microsomal electron transport Chapter 14). An enzyme-bound superoxide radical is responsible for the oxidation of acyl-CoA. Four desaturases specific for introducing cis double bonds at C9, Ca, C5, and C4, respectively, are known. If the substrate is saturated, the first double bond introduced is C9. With an unsaturated substrate, other double bonds are introduced between the carboxyl group and the double bond nearest the carboxyl group. Desaturation yields a divinylmethane arrangement of double bonds (—CH=CH—CH2—CH=CH—). Usually desaturation alternates with chain elongation. Desaturation is inhibited by fasting and diabetes. The oxidation of unsaturated fatty acids occurs in mitochondria. 

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