Enzyme acyl-CoA dehydrogenase

Degradation of unsaturated fatty acids is primarily by the p-oxidation pathway. However, the presence of double bonds necessitates additional steps, P-Oxidation proceeds until a cis double bond occurs in the position (between C-3 and C-4). The enzyme acyl-CoA dehydrogenase cannot utilize a compound with such a configuration as a substrate and so an additional enzyme, dodece-noyl-CoA A-isomerase is required to convert the... 

A summary of the sequential reactions of the -oxidation cycle and the relationship of the overall process to energy metabolism in mitochondria is shown in Figure 3.20. Two carbon units (as acetyl-CoA) are removed from the fatty acyl-Co A substrate by the successive action of four enzymes - acyl-CoA dehydrogenase, enoyl hydratase, a second dehydrogenase and a thiolase. These enzymes are detailed in Table 3.12. 

The first step in the )8-oxidation cycle proper is the introduction of a tram-a,p double bond into the hydrocarbon chain of the activated fatty acid, catalysed by the flavoprotein enzyme, acyl-CoA dehydrogenase. 

FIGURE 21.V The fatty acyl-CoA dehydrogenase reaction, emphasizing that the reaction involves reduction of enzyme-bonnd FAD (indicated by brackets). 

This is a crucial point because (as we will see) proton transport is coupled with ATP synthesis. Oxidation of one FADHg in the electron transport chain results in synthesis of approximately two molecules of ATP, compared with the approximately three ATPs produced by the oxidation of one NADH. Other enzymes can also supply electrons to UQ, including mitochondrial 5w-glyc-erophosphate dehydrogenase, an inner membrane-bound shuttle enzyme, and the fatty acyl-CoA dehydrogenases, three soluble matrix enzymes involved in fatty acid oxidation (Figure 21.7 also see Chapter 24). The path of electrons from succinate to UQ is shown in Figure 21.8. 

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... 

Enzymes 7,9, and 13 form a trifunctional protein associated with the inner face of the inner mitochondrial membrane. Very-long-chain acyl-CoA dehydrogenase is also associated with other inner mitochondrial membranes while the other enzymes are in the matrix and may be loosely associated with the inner face of the inner membrane. A medium-chain 2-enoyl-CoA hydratase may also be present in the mitochondrial matrix. 

The oxidation of fatty acids within the Knoop-Lynen cycle occurs in the matrix. The Knoop-Lynen cycle includes four enzymes that act successively on acetyl-CoA. These are acyl-CoA dehydrogenase (FAD-dependent enzyme), enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (NAD-dependent enzyme), and acetyl-CoA acyltrans-ferase. Each turn, or revolution, of the fatty acid spiral produces... 

This enzyme [EC 1.3.99.2], also referred to as short-chain acyl-CoA dehydrogenase and unsaturated acyl-CoA reductase, catalyzes the reaction of butanoyl-CoA and an electron-transferring fiavoprotein to produce... 

Thorpe, C. Kim, J.J. (1995) Structure and mechanism of action of the acyl-CoA dehydrogenases. FASEB J. 9, 718-725. Short, clear description of the three-dimensional structure and catalytic mechanism of these enzymes. 

Bole of FAD as Electron Acceptor Acyl-CoA dehydrogenase uses enzyme-bound FAD as a prosthetic group to dehydrogenate the a and j3 carbons of fatty acyl-CoA. What is the advantage of using FAD as an electron acceptor rather than NAD+ Explain in terms of the standard reduction potentials for the Enz-FAD/EADH2 (E ° = —0.219 V) and NAD+/NADH (E ° = —0.320 V) half-reactions. 

The branched-chain fatty acid, phytanic acid, is not a substrate for acyl CoA dehydrogenase due to the methyl group on its third (P) carbon (Figure 16.22). Instead, it is hydroxylated at the a-carbon by fatty acid a-hydroxylase. The product is decarboxylated and then activated to its CoA derivative, which is a substrate for the enzymes of P-oxidation. [Note Refsum disease is a rare, autosomal recessive disorder caused by a deficiency of a-hydroxylase. This results in the accumulation of phytanic acid in the plasma and tissues. The symptoms are primarily neurologic, and the treatment involves dietary restriction to halt disease progression.]... 

However, these experiments may not have established a mechanism for natural flavoprotein catalysis because the properties of 5-deazaflavins resemble those of NAD+ more than of flavins.239 Their oxidation-reduction potentials are low, they do not form stable free radicals, and their reduced forms don t react readily with 02. Nevertheless, for an acyl-CoA dehydrogenase the rate of reaction of the deazaflavin is almost as fast as that of natural FAD.238 For these enzymes a hydride ion transfer from the (3 CH (reaction type D of Table 15-1) is made easy by removal of the a-H of the acyl-CoA to form an enolate anion intermediate. 

Acyl-CoA dehydrogenase 766, 785,789 Acyl-dihydrolipoyl derivative 736 Acyl-enzyme... 

For every step of the P oxidation sequence there is a small family of enzymes with differing chain length preferences.6 7 For example, in liver mitochondria one acyl-CoA dehydrogenase acts most rapidly on M-butyryl and other short-chain acyl-CoA a second prefers a substrate of medium chain length such as n-octanoyl-CoA a third prefers long-chain substrates such as pal-mitoyl-CoA and a fourth, substrates with 2-methyl branches. A fifth enzyme acts specifically on isovaleryl-CoA. Similar preferences exist for the other enzymes of the P oxidation pathway. In Escherichia coli... 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

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