3.5- dienoyl-CoAs

Dienoyl-CoAs might be generated fortuitously by A, A -enoyl-CoA isomerase acting on 2,5-dienoyl-CoAs that are normal P-oxidation intermediates of unsaturated fatty acids with odd-numbered double bonds. However, 3,5-dodecadienoyl-CoA is an obligatory metabolite of 9-cis,ll-trans-octadecadienoic acid, also referred to as conjugated linoleic acid, which is a minor fatty acid of the human diet. 

Degradation of Polyunsaturated Fatty Acids Requires 2,4-Dienoyl-CoA Reductase... 

Polyunsaturated fatty acids pose a slightly more complicated situation for the cell. Consider, for example, the case of linoleic acid shown in Figure 24.24. As with oleic acid, /3-oxidation proceeds through three cycles, and enoyl-CoA isomerase converts the cA-A double bond to a trans-b double bond to permit one more round of /3-oxidation. What results this time, however, is a cA-A enoyl-CoA, which is converted normally by acyl-CoA dehydrogenase to a trans-b, cis-b species. This, however, is a poor substrate for the enoyl-CoA hydratase. This problem is solved by 2,4-dienoyl-CoA reductase, the product of which depends on the organism. The mammalian form of this enzyme produces a trans-b enoyl product, as shown in Figure 24.24, which can be converted by an enoyl-CoA isomerase to the trans-b enoyl-CoA, which can then proceed normally through the /3-oxidation pathway. Escherichia coli possesses a... 

FIGURE 24.24 The oxidation pathway for polyunsaturated fatty adds, illustrated for linoleic add. Three cycles of /3-oxidation on linoleoyl-CoA yield the cis-A, d.s-A intermediate, which is converted to a tran.s-A, cis-A intermediate. An additional round of /S-oxi-dation gives d.s-A enoyl-CoA, which is oxidized to the trans-A, d.s-A species by acyl-CoA dehydrogenase. The subsequent action of 2,4-dienoyl-CoA reductase yields the trans-A product, which is converted by enoyl-CoA isomerase to the tran.s-A form. Normal /S-oxida-tion then produces five molecules of acetyl-CoA. 

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 requires two additional enzymes enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. Odd-number fatty acids are oxidized by the /3-oxidation pathway to yield acetyl-CoA and a molecule of propionyl-CoA This is carboxylated to methylmalonyl-CoA, which is isomerized to succinyl-CoA in a reaction catalyzed by methylmalonyl-CoA mutase, an enzyme requiring coenzyme B12. 

Unsaturated fatty acids. Mitochondrial P oxidation of such unsaturated acids as the A9-oleic acid begins with removal of two molecules of acetyl-CoA to form a A5-acyl-CoA. However, further metabolism is slow. Two pathways have been identified (Eq. 17-l).26 29b The first step for both is a normal dehydrogenation to a 2-fraus-5-czs-dienoyl-CoA. In pathway I this intermediate reacts slowly by the normal p oxidation sequence to form a 3-czs-enoyl-CoA intermediate which must then be acted upon by an auxiliary enzyme, a ds-AMra s-A2-enoyl-CoA isomerase (Eq. 17-1, step c), before P oxidation can continue. 

The alternative reductase pathway (II in Eq. 17-1) is often faster. It makes use of an additional isomerase which converts 3-trans, 5-czs-dienoyl-CoA into the 2-1vans, 4-trans isomer in which the double bonds are conjugated with the carbonyl group.29 This permits removal of one double bond by reduction with NADPH as shown (Eq. 17-1, step/).29a 29b The peroxisomal... 

As many as 1 in 10,000 persons may inherit such prob-lems.48 50a Tire proteins that may be defective include a plasma membrane carnitine transporter carnitine palmitoyltransferases camitine/acylcamitine trans-locase long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases 2,4-dienoyl-CoA reductase (Eq. 17-1) and long-chain 3-hydroxyacyl-CoA dehydrogenase. Some of these are indicated in Fig. 17-2. 

Polyunsaturated fatty acids are also degraded by [3 oxidation, but the process requires enoyl-CoA isomerase and an additional enzyme, 2,4-dienoyl-CoA reductase (fig. 18.6). For example, the degradation of linoleoyl-CoA (18 2A9-12) begins, like that of oleoyl-CoA, with three rounds of /3 oxidation and results in a A3-cis unsaturated fatty acyl-CoA that is not a substrate for acyl-CoA dehydrogenase. Isomerization of the double bond to the A2-trans position by enoyl-CoA isomerase allows the resumption of... 

Polyunsaturated fatty acids such as linoleoyl-CoA are also oxidized in the mitochondria. In addition to the enzymes of oxidation and enoyl-CoA isomerase, the process requires 2,4-dienoyl-CoA reductase. 

A2-tran.v-isomer by enoyl-CoA isomerase (see fig. 18.6). With the double bond in the A2-tra s-configuration, /3 oxidation can resume. As with the oxidation of oleoyl-CoA, one less FADH2 and 1.5 fewer ATPs are produced in the oxidation of linoleoyl-CoA compared to stearoyl-CoA. In addition, one NADPH is required for the reduction of the dienoyl-CoA. Hence, in balancing the yield for complete oxidation of linoleoyl-CoA, one less NADH would be available to the respiratory chain and, therefore, 2.5 fewer ATPs would be produced. This is true since the two nucleotides can be interconverted ... 

Another enzyme, in addition to the isomerase, is required for the oxidation of polyunsaturated fatty acids which have a double bond at an even-numbered carbon atom. In this case the 2,4-dienoyl intermediate resulting from the action of acyl CoA dehydrogenase is acted on by 2,4-dienoyl CoA reductase to form c/s-A3-enoyl CoA (Fig. 4). This is then converted by the isomerase into the trans form which continues down the pathway. These reactions are important since over half the fatty acids of plant and animal lipids are unsaturated (and often polyunsaturated). 

After one further -oxidation cycle, a 4-cis-enoyl CoA intermediate is formed. It is acted upon by enoyl-CoA dehydrogenase to give 2-trans, 4-cis-dienoyl CoA. Further metabolism of this intermediate proceeds through one cycle of /3-oxidation and requires a second auxiliary enzyme, 2,4-dienoyl-CoA reductase which has high activity in mitochondria. Thus, nine molecules of acetyl-CoA are produced from the oxidation of linoleic acid. 

Very long chain fatty acids are initially oxidized in the peroxisome where the initial oxidation step is catalyzed by acyl-CoA oxidase and the subsequent steps in fS-oxidation are catalyzed by a multi-enzyme complex with hydratase, dehydo-genase, and thiolase activities. Unsaturated fatty acids require additional enzymatic activities, including enoyl-CoA isomerase and dienoyl-CoA reductase. Readers are directed to Vance and Vance (2) for additional details regarding fi-oxidation, including the details of the metabolic reactions. 

Figure 22.10. Oxidation of Linoleoyl CoA. The complete oxidation of the diunsaturated fatty acid linoleate is facilitated by the activity of enoyl CoA isomerase and 2,4-dienoyl CoA reductase.

Two new enzymes are required to handle these situations Enoyl-CoA isomerase (isomerizes a cis-3,4-double bond to a frflns-2,3-double bond), and 2,4-Dienoyl-CoA reductase (reduces the ds-4,5-double bond in the trans-2,3-ds-4,5-dienoyl-CoA derivative formed during feta-oxidation). The resulting products are then broken down by the feta-oxidation enzymes. 

DienoyhGoA reductase deficiency 222745 Dienoyl-CoA reductase <1 100,000 Myopathy 00000M 0000 ... 

Glutaric acidemia type II is caused by defects in the ETF/ETF-QO proteins. The clinical manifestations of these disorders are similar to medium-chain acyl-CoA dehydrogenase deficiency (discussed later). The double bond formed by the acyl-CoA dehydrogenase has a trans configuration. The double bonds in naturally occurring fatty acids are generally in the cis configuration. The oxidation of unsaturated m-fatty acids requires two auxiliary enzymes, enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. 

Oxidation of unsaturated fatty acids requires A -cis-,A -trans-enoyl-CoA isomerase and NADPH-dependent 2,4-dienoyl-CoA reductase, in addition to the enzymes of y3-oxidation. The enoyl-CoA isomerase produces the substrate for the hydration step. The reductase catalyzes the reduction of A -frans-,A -cjs-decadienoyl-CoA to A -rrans-decenoyl-CoA. The latter is isomerized to A -trans-decenoyl isomerase, which is a normal -oxidation intermediate. These reactions are illustrated for oxidation of oleic and linoleic acids in Figures 18-7 and 18-8. 

Another problem arises with the oxidation of polyunsaturated fatty acids. Consider linoleate, a Cx polyunsaturated fatty acid with cis-A and cis-A double bonds (Figure 22.11). The cis-A double bond formed after three rounds of P oxidation is converted into a trans-A" double bond by the aforementioned isomerase. The acyl (ioA produced by another round of P oxidation contains a cis-A double bond. Dehydrogenation of this species by acy] CoA dehydrogenase yields a. 2,4-dienoyl intermediate, which is not a substrate for the next enzyme in the p-oxidation pathway. This impasse is circumvented by 2,4-dienoyl CoA reductase, an enzyme that uses to reduce the 2,4-dienoyl intermediate to trans-A -enoyl CoA. ds-A Enoyl CoA isomerase then converts trans-A -enoyl CoA into the trans-A form, a customary intermediate in the P-oxidation pathway. These catalytic... 

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