P Oxidation pathway

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

The degradation of 11,12-methyleneoctadecanoate is carried out in Tetrahymena pyri-formis by a modified p-oxidation pathway with the formation of propionate and acetate (Figure 7.34a) (Tipton and Al-Shather 1974). 

The chain shortening pathway has not been characterized in detail at the enzymatic level in insects. It presumably is similar to the characterized pathway as it occurs in vertebrates. These enzymes are a partial P-oxidation pathway located in peroxisomes [29]. The key enzymes involved are an acyl-CoA oxidase (a multifunctional protein containing enoyl-CoA hydratase and 3-hy-droxyacyl-CoA dehydrogenase activities) and a 3-oxoacyl-CoA thiolase [30]. These enzymes act in concert to chain shorten acyl-CoAs by removing an acetyl group. A considerable amount of evidence in a number of moths has accumulated to indicate that limited chain shortening occurs in a variety of pheromone biosynthetic pathways. 

The major hormone-sensitive control point for the mobilization of fat and the p-oxidation pathway is the effect of phosphorylation on the activity of the hormone-sensitive lipase of the adipose tissue. The major direct control point for p oxidation is the inhibition of carnitine acyl-... 

In liver cells, two P-oxidation pathways are present one in mitochondria and a slightly different pathway in peroxisomes. 

As a general mechanism, the degradation of PVA starts outside the cells via enzymatic attack on the polymer. The resulting products are a mixture of acetoxy hydroxy and hydroxy fatty acids. Upon intracellular enzymatic deacetylation, hydroxy fatty acids are generated that can be further metabolised via the classical p-oxidation pathway and TCA cycle. 

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. 

Describe the parallel reaction sequences between the citric acid cycle and the P oxidation pathway. 

The net result is exactly the same as that of the (3 oxidation pathway, but for this microorganism, the pathway is demonstrably different in that pentanal, CH3(CH2)3CHO, is an intermediate in the sequence. Which enzyme(s) of the P oxidation pathway does this microorganism lack Propose an enzymatic reaction to account for the formation of this intermediate and a series for its conversion to the acyl CoA. ATP is not required. 

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... 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

Mention of mitochondria usually brings to the mind of the biochemist the citric add cyde, the P oxidation pathway of fatty acid metabolism, and oxidative phosphorylation. 

Biosynthesis occurs from 3-hydroxybutyryl-CoA. Some bacteria incorporate other P-hydroxyac-ids into the polymer.f Apparently various hydroxy-acyl-CoAs can be diverted from the P oxidation pathway to polymer synthesis, and synthases that will accept a variety of P-hydroxyacyl-CoA substrates have been isolated. h i More than 80 different hydroxyacyl groups can be incorporated into the polymer.1 A bacterially produced copolymer of P-... 

In target tissues, fatty acids are broken down through the P-oxidation pathway that releases 2-carbon units in succession. For example, palmitic acid has 16 carbons. Its initial oxidation produces eight acetyl-Coenzyme A (CoA) molecules, eight reduced FAD molecules, and eight NADH molecules. The fatty acid is first activated at the outer mitochondrial surface by conjugating it with CoA, then... 

A fatty acid with n carbons yields nil acetyl CoA molecules after (nil - 1) passages of the p-oxidation pathway. 

The P-oxidation pathway accomplishes the complete degradation of saturated fatty acids having an even number of carbon atoms. Most fatty acids have such structures because of their mode of synthesis (Section 22.4.3). However, not all fatty acids are so simple. The oxidation of fatty acids containing double bonds requires additional steps. Likewise, fatty acids containing an odd number of carbon atoms yield a propionyl CoA at the final thiolysis step that must be converted into an easily usable form by additional enzyme reactions. 

A different pathway in a different compartment degrades fatty acids. Carnitine transports fatty acids into mitochondria, where they are degraded to acetyl CoA in the mitochondrial matrix by P-oxidation. The acetyl CoA then enters the citric acid cycle if the supply of oxaloacetate is sufficient. Alternatively, acetyl CoA can give rise to ketone bodies. The FADH2 and NADH formed in the P-oxidation pathway transfer their electrons to O2 through the electron-transport... 

Earlier, it was thought that fatty acid biosynthesis occurred by reversal of the P-oxidation pathway. On the contrary, it occurs by a separate pathway that differs from P-oxidation in several ways. 

Biomimetic studies of this proposed cascade have provided further tantalising, albeit incomplete, supporting evidence [81]. Feeding studies with a NAC thioester of the required (E,E,E)-triene intermediate 42 in labeled form have so far been unsuccessful, although this may well be due to problems of transport across the cell membrane and degradation by p-oxidation pathways [82]. 

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... 

Recent studies have indicated that in addition to mitochondria, peroxisomes are capable of removing acetyl-CoA moieties from long-chain fatty acids. The peroxisomal P-oxidative pathway is different in two major respects from the mitochondrial system. First, the hydrogen atoms removed are oxidized to water via H2O2. This process does not generate energy in the form of ATP. Second, peroxisomal P-oxidation stops when octanoyl-CoA (C8-C0A) is produced. 

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