Very long chain fatty acids oxidation

In contrast to the general peroxisome biogenesis defects, patients with X-linked adrenoleucodystrophy, whose very-long-chain fatty acid oxidation is impaired as a result of an uptake defect, show minimal abnormalities of their DHA levels. 

A deficiency of very long-chain fatty acid oxidation in peroxisomes is apparently caused by a defective transporter of the ABC type (Chapter 8).55 The disease, X-linked adrenoleukodystrophy (ALD), has received considerable publicity because of attempts to treat it with "Lorenzo s oil," a mixture of triglycerides of oleic and the C22 monoenoic erucic acid. The hope has... 

Peroxisomes Oxidize Very Long Chain Fatty Acids... 

A modified form of P-oxidation is found in peroxisomes and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by catalase. Thus, this dehydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. The system facilitates the oxidation of very long chain fatty acids (eg, Cjq, C22). These enzymes are induced by... 

Figure22-10. Regulation of long-chain fatty acid oxidation in the liver. (FFA, free fatty acids VLDL, very low density lipoprotein.) Positive ( ) and negative ( ) regulatory effects are represented by broken arrows and substrate flow by solid arrows.

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. 

Peroxisomes are organelles which are bounded by a single membrane. They are present in the Uver where very long-chain fatty acids are oxidised by P-oxidation in peroxisomes, which is different from mitochondrial oxidation. 

The capacity of P-oxidation in about 10% of that in the mitochondria but it plays an important role in oxidising unusual fatty acids for example, very long-chain fatty acids, polyunsaturated fatty acids, dicarbox-ylic fatty acids. 

F. Oxidation of very long-chain fatty acids (VLCFAs), ie, fatty acids having >22 carbons, requires special enzymes located in the peroxisome. 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

In mitochondria, there are four fatty acyl CoA dehydrogenase species, each of which has a specificity for either short-, mediurr-long-, or very-long-chain fatty acids. MCAD deficiency, an autos mal, recessive disorder, is one of the most common inborn errors of metabolism, and the most common inborn error of fatty add oxidation, being found in 1 in 12,000 births in the west, and 1 in 40,000 worldwide. It causes a decrease in fatty acid oxidation and severe hypoglycemia (because the tissues cannot obtain full ener getic benefit from fatty acids and, therefore, must now rely on glu cose). Treatment includes a carbohydrate-rich diet. [Note Infants are particularly affected by MCAD deficiency, because they rely for their nourishment on milk, which contains primarily MCADs. 

A significant amount of /3 oxidation takes place in the peroxisomes. These structures specialize in the oxidation of "very long chain" fatty acids (20 carbons or more). They enter the peroxisomes as CoA derivatives, and no carnitine is required for the transfer from cytosol. Peroxisomal /3-oxidation enzymes differ from those of mitochondria, although they perform the same functions except for the first (unsaturation) step. Instead of using mitochondria-like FAD-dehydroge-... 

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. 

Process of oxidation of very-long-chain fatty acids in peroxisomes... 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

Fig. 1. Metabolic pathway of essential fatty acids. Recent evidence indicated that 22 6n-3 are produced by [l-oxidation of 24 6n-3, which is desaturated from 24 5n-3, after elongation from 22 5n-3. Very long-chain fatty acids in the box are found in the retina however, the metabolism and function is not known.

OXIDATION IN PEROXISOMES /FOxidation of fatty acids also occurs within peroxisomes. In animals peroxisomal /Foxidation appears to shorten very long-chain fatty acids. The resulting medium-chain fatty acids are further degraded within mitochondria. In many plant cells, /Foxidation occurs predominantly in peroxisomes. (Fatty acids are not an important source of energy in most plant tissues. Although some plant mitochondria contain /Foxidation enzymes, this pathway is not... 

Peroxisomal membrane possesses an acyl-CoA ligase activity that is specific for very long-chain fatty acids. Mitochondria apparently cannot activate long-chain fatty acids such as tetracosanoic (24 0) and hexacosanoic (26 0). Peroxisomal carnitine acyltransferases catalyze the transfer of these molecules into peroxisomes, where they are oxidized to form acetyl-CoA and medium-chain acyl-Co A molecules (i.e., those possessing between 6 and 12 carbons). Medium-chain acyl-Co As are further degraded via /3-oxidation within mitochondria. 

In the human genetic disease X-linked adreno-leukodystrophy (ADL), peroxisomal oxidation of very long chain fatty acids is defective. The ADL gene encodes the peroxisomal membrane protein that trans-... 

Several human genetic diseases are associated with defective ABC proteins. X-llnked adrenoleukodys-trophy (ALD), for Instance, is characterized by a defective ABC transport protein (ABCDl) that is localized to peroxisomal membranes. This protein normally regulates Import of very long chain fatty acids into peroxisomes, where they undergo oxidation in its absence these fatty acids accumulate in the cytosol and cause cellular damage. Tanglers disease is marked by a deficiency of the plasma-membrane ABC protein (ABCAl) that transports phospholipids and possibly cholesterol (Chapter 18). 

In most eukaryotic cells, oxidation of fatty acids, especially very long chain fatty acids, occurs primarily In per-... 

ABCDl Ubiquitous in peroxisomal membrane Influences activity of peroxisomal enzyme that oxidizes very long chain fatty acids Adrenoleukodys trophy (ADL)... 

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. 

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