P-oxidation of unsaturated fatty acids

More recent is the observation that odd-numbered double bonds can be reduced at the stage of 5-enoyl-CoA intermediates that are formed during the P-oxidation of unsaturated fatty acids. Shown in Fig. 4 is the sequence of reactions that explains the NADPH-dependent reduction of S-cw-enoyl-CoA (I) [17]. The introduction of a 2-trans double bond by acyl-CoA dehydrogenase yields 2,5-dienoyl-CoA (II), part of which is converted... 

Smeland, T.E., Nada, M., Cuebas, D., Schulz, H. 1992. NADPH-dependent p-oxidation of unsaturated fatty acids with double bonds extending from odd-numbered carbon atoms. Pmc. Natl. Acad. Sci. USA 89 6673-6677. 

CoA oxidase, 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase. Dietary sesamin also increased the activity of 2,4-dienoyl-CoA reductase and A, A -enoyl-CoA isomerase, enzymes involved in the auxiliary pathway for p-oxidation of unsaturated fatty acids [246], On the other hand, the results obtained by Fukuda et al. [247] suggest that increased fatty acid oxidation by dietary sesamin leads to decreased esterification of fatty acids and reduces the synthesis and secretion of triacylglycerol. 

FIGURE 21.9 P-oxidation of unsaturated fatty acids. In the case of oleoyl-CoA, three P-oxidation cycles produce three molecules of acetyl-CoA and leave as A -dodecenoyl-CoA. Rearrangement of enoyl-CoA isomerase gives the trans-A species, which then proceeds normally through the P-oxidation pathway. 

You, S.Y., Cosloy, S. Schulz, H. (1989) J. Biol Chem., 264, 16489-16495, Evidence for the essential function of 2,4-dienoyl-coenzyme A reductase in the P-oxidation of unsaturated fatty acids in vivo. 

Shoukry, K. Schulz, H. (1998) J. Biol. Chem., 273, 6892-6899, Significance of the reductase-dependent pathway for the p-oxidation of unsaturated fatty acids with odd-numbered double bonds. 

Ensenauer, R., He, M., Willard, J.M., Goetzman, E.S., Corydon, T.J., Vandahl, B.B., Mohsen, A.W., Isaya, G., and Vockley, J., 2005. Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial p-oxidation of unsaturated fatty acids. The Journal of Biological Chemistry. 280 32309-32316. 

A%A-Enoyl-CoA isomerase activity (EC 5.3.3.8) was first demonstrated in isolated rat liver mitochondria by Stoffel and coworkers. The enzyme catalyzes the conversion of both cis and tra 5-3-enoyl-CoA esters to their trans-2 counterparts with the catalytic rate being about ten times higher for cw-enoyl-CoA substrates. Originally, isomerase was regarded as an obligatory enzyme for the metabolism of monounsaturated and polyunsaturated fatty acids with double bonds at odd-numbered carbon atoms, e.g. oleic, linolenic and arachidonic acids. However, according to recent data, isomerase also participates in the P-oxidation of unsaturated fatty acids with double bonds at even-numbered position, since A intermediates arise from double bonds at the A -position via a 2,4-dienoyl-CoA reductase-dependent pathway" (see below). 

Figure 22-4. Sequence of reactions in the oxidation of unsaturated fatty acids, eg, linoleic acid. A -c/s-fatty acids or fatty acids forming A -c/s-enoyl-CoA enter the pathway at the position shown. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrial sources such as glutamate dehydrogenase, isocitrate dehydrogenase,and NAD(P)H transhydrogenase.

OXIDATION OF UNSATURATED FATTY ACIDS OCCURS BY A MODIFIED P-OXIDATION PATHWAY... 

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. 

A rise in free fatty acids may also cause changes in the flavour components. Increased P-oxidation of the free fatty acids leads to P-keto acids which are decarboxylated to methyl ketones. There are also increases in unsaturated aldehydes, especially 2-enals and 2,4-dienals, probably formed by oxidation of unsaturated fatty acids. This marked increase in carbonyls and unsaturated aldehydes may cause a significant alteration in the flavour, as these compounds have considerable organoleptic properties. 

When measuring the mitochondrial P-oxidation in liver, 2-methyl EPA did not cause any effect compared to EPA or control, while the other EPA-derivatives increased the fatty acid oxidation in mitochondria. We measured the mitochondrial activity and gene expression of an enzyme involved in the oxidation of unsaturated fatty acids, the 2,4-dienoyl-CoA reductase. Both the activity and gene expression seemed to increase in rats fed 2,2-dimethyl EPA. We also measured the total activity of CPT in liver, and found an increased activity in rats fed 2,2-dimethyl EPA. The increase in total CPT-activity after administration of 2,2-dimethyl EPA seemed to be due to the observed increase in CPT-II transcription, as the mRNA level of CPT-I was unchanged (data to be published). The peroxisomal P-oxidation, the activity and gene e q)ression of fatty acyl-CoA oxidase, the rate-limiting enzyme of peroxisomal P-oxidation, and the gene expression of the peroxisomal multifunctional protein were increased after administration of the EPA-derivatives, as shown in Table 2. 

In experiments with different inhibitors of mitochondrial fatty acid oxidation we were intrigued by finding that 4-pentenoate had lost completely its inhibitory effect on fatty acid oxidation in hepatocytes from clofibrate-fed rats [11], The P-oxidation of 4-pentenoate will give pent-2,4-dienoyl-CoA. This reminded us of the work by Kunau and Dommes [12] who detected the enzyme 2,4-dienoyl-CoA reductase. The 2,4-dienoyl-CoA esters with their conjugated double bonds are poorly hydrated by crotonase in the P-oxidation reaction sequence, and Kunau and Dommes suggested that their enzyme, converting the 2,4-dienoyl-CoA ester to a 3-enoyl-CoA by reduction with NADPH, take part in the oxidation of unsaturated fatty acids with double bonds at equal-numbered positions. Thus, the oxidation of these fatty acids should paradoxically depend on a reduction step. 

Chan, H., Photosensitized oxidation of unsaturated fatty acid methyl esters the identification of different pathways, J. Amer. Oil Chem. Soc., 54, p. 100, 1977. 

In lipid metabolism, ds-trans isomerism is particularly important. For example, double bonds in natural fatty acids (see p.48) usually have a as configuration. By contrast, unsaturated intermediates of p oxidation have a trans configuration. This makes the breakdown of unsaturated fatty acids more complicated (see p. 166). Light-induced cis-trans isomerization of retinal is of central importance in the visual cycle (see p.358). 

Most fatty acids are saturated and even-numbered. They are broken down via p-oxidation (see p.l64). In addition, there are special pathways involving degradation of unsaturated fatty acids (A), degradation of fatty acids with an odd number of C atoms (B), a and ro oxidation of fatty acids, and degradation in peroxisomes. 

The renal cytochrome P-450 enzyme system is involved in oxidative reactions in which an atom of molecular oxygen is inserted in an organic molecule. The flavoprotein NADPH-cytochrome P-450 reductase is an essential component of the mixed-function oxidase systems (MFO). Microsomal membranes appear to be particularly subject to attack by reactive oxygen radicals due to their high content of unsaturated fatty acids and the presence of the cytochrome P-450 system [40]. Cephaloridine-induced peroxidation of membrane lipids is decreased by the cytochrome P-450 inhibitor cobalt chloride [31], suggesting a role for a cytochrome P-450 reductase in the P-lactam-induced generation of reactive oxygen species and subsequent peroxidation products. 

Riserus, U., Basu, S., Jovinge, S., Fredrikson, G.N., Aralov, J., and Vessby, B. 2002. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein A potential link to fatty acid-induced insulin resistance. Circulation 106, 1925-1929. Rossetti, R.G., Seiler, C.M., DeLuca, P., Laposata, M., and Zurier, R.B. 1997. Oral administration of unsaturated fatty acids Effects on human peripheral blood T lymphocyte proliferation. J. Leukoc. Biol 62, 438-443. 

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