Peroxisomal P-oxidation pathways

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. 

Fatty acid breakdown is mainly accomplished via the mitochondrial and the peroxisomal p-oxidation pathways (Fig. 1.3). While short-chain and medium-chain fatty acids are mainly degraded in the mitochondria, very long-chain fatty acids (more than 20 carbons) are first shortened in the peroxisomes and then usually further oxidized in the mitochondria. 

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. 

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

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

Poirier, Y., Antonenkov, V.D., Glumoff, T., Hiltunen, J.K. 2006. Peroxisomal p-oxidation — a metabolic pathway with multiple functions. Biochim. Biophys. Acta 1763 1413-1426. 

It is not clear why cholesterol synthesis might be compartmentalized such that intermediates cycle between peroxisomes and the cytosol. One possibility is to permit the shunting of acetyl-CoA derived from peroxisomal p-oxidation of long-chain fatty acids preferentially into the cholesterol biosynthetic pathway rather than allowing it to be released into the cytosol for incorporation into cellular fatty acids (W.J. Kovacs, 2006). 

Fatty acids are a major fuel in the body. After eating, we store excess fatty acids and carbohydrates that are not oxidized as fat (triacylglycerols) in adipose tissue. Between meals, these fatty acids are released and circulate in blood bound to albumin. In muscle, liver, and other tissues, fatty acids are oxidized to acetyl CoA in the pathway of 3-oxidation. NADH and FAD(2H) generated from 3-oxidation are reoxidized by O2 in the electron transport chain, thereby generating ATP (see Fig. 2). Small amounts of certain fatty acids are oxidized through other pathways that convert them to either oxidizable fuels or urinary excretion products (e.g., peroxisomal P-oxidation). 

The octanoyl CoA that is the end-product of peroxisomal oxidation leaves the peroxisomes and the octanoyl group is transferred through the inner mitochondrial membrane by medium-chain-length acylcarnitine transferase. In the mitochondria, it enters the regular p-oxidation pathway, beginning with medium-chain-length acyl CoA dehydrogenase (MCAD). 

Compared with controls, 22 6n-3 biosynthesis was normal in cells from patients with deficiencies of the mitochondrial fatty acid p-oxidation enzymes, vay-long-chain acyl-CoA dehydrogenase (VLCAD) or medium-chain acyl-Co A dehydrogenase (MCAD) (Table 2). These findings confirmed that retro-conversion of 24 6n-3 to 22 6n-3 is via the peroxisomal, but not mitochondrial fatty acid p-oxidation pathway. 

When the synthesis of lipids is reduced due to the presence of fatty acid analogs, the NEFAs will be diverted from the esterification pathway. The level of NEFAs in the hepatocytes treated with 3-thia fatty acids tended to decrease. This indicates that the mitochondrial P-oxidation was increased, as the peroxisomal P-oxidation was unchanged in these hepatocytes. Thus, it is likely that the non-P-oxidizable fatty acid analogs reduced the availability of fatty acids for TG-synthesis due to increased mitochondrial fatty oxidation. The lack of effect on the peroxisomal P-oxidation confirms the in vivo data that the hypotriglyceridemic effect of the analogs can be dissociated from the proliferation of peroxisomes." ... 

Filppula, SA., Sormunen, R.T., Hartig, A., Kunau, W.-H. Hiltunen, J.K. (1995) J. Biol Chem. 270, 27453-27457. Changing stereochemistry for a metabolic pathway in vivo. Experiments with the peroxisomal P-oxidation in yeast. 

Abstract Synthesis of polyhydroxyalkanoates (PHAs) in crop plants is viewed as an attractive approach for the production of this family of biodegradable plastics in large qnantities and at low costs. Synthesis of PHAs containing various monomers has so far been demonstrated in the cytosol, plastids, and peroxisomes of plants. Several biochemical pathways have been modified to achieve this, including the isoprenoid pathway, the fatty acid biosynthetic pathway, and the fatty acid P-oxidation pathway. PHA synthesis has been demonstrated in a number of plants, including monocots and dicots, and np to 40% PHA per gram dry weight has been demonstrated in Arabidopsis thaliana. Despite some successes, production of... 

In the second trial conducted by Murata et al. (1997), varying amounts of dietary TAG were replaced by DAG while the dietary fatty acid content was maintained at 9.39 g/100 g diet. After 21 days on the new diets, significant reductions in serum and liver TAG levels were found in the groups of rats fed diets in which DAG supplied more than 6.58 gfatty acids/100 g diet. Reductions in the activities of enzymes involved in fatty acid synthesis and increases in palmitoyl-CoA oxidation rates by both mitochondrial and peroxisomal pathways were also apparent when DAG replaced TAG in diets to supply more than 6.58 g fatty acid/100 g diet. Increasing dietary levels of DAG progressively increased the activities of enzymes involved in the P-oxidation pathway in the liver, including carnitine palmitoyltransferase (EC 2.3.1.21), acyl-CoA... 

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. 

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. 

Sharma R, Lake BG, Gibson GG. 1988. Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid -oxidation pathway in therat by clofibrate and di-(2-ethylhexyl)phthalate. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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