Fatty acids, long-chain peroxisomal

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... 

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... 

Al-Dirbashi, O.Y. et al., Rapid UPLC-MS/MS method for routine analysis of plasma pristanic, phytanic, and very long chain fatty acid markers of peroxisomal disorders, J. Lipid Res., 49(8), 1855, 2008. 

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... 

Interest in import of proteins into peroxisomes has been stimulated by studies on Zellweger syndrome. This condition is apparent at birth and is characterized by profound neurologic impairment, victims often dying within a year. The number of peroxisomes can vary from being almost normal to being virtually absent in some patients. Biochemical findings include an accumulation of very long chain fatty acids, abnormalities of... 

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. 

Adrenoleukodystrophy is an X-linked dysmyelinative disorder caused by mutations in the ABCD1 gene, which encodes the peroxisomal integral membrane ALD protein, a member of the ATP binding cassette transporter family. These mutations result in impaired clearance of plasma very-long-chain fatty acids. Affected males may present with symmetrical distal axonal polyneuropathy, adrenocortical insufficiency or CNS demyelination, while occasional heterozygous women demonstrate deficits suggestive of multiple sclerosis [56]. Manipulation of dietary fatty acid intake has some minimal therapeutic effect, while bone marrow transplantation has diminished deficits in a few patients. (See in Ch. 41.)... 

Adrenoleukodystrophy X-linked Peroxisomal membrane protein in the ABC transporter family Decreased peroxidation of saturated, very-long-chain fatty acids, causing their accumulation in brain, adrenals and other tissues variable phenotypes with regard to hypomyelination see text 1,26, Ch. 40... 

A separate very long-chain-acyl-CoA synthetase is present in peroxisomes for the activation of very long-chain fatty acids, such as arachidonate (20 carbon atoms). These fatty acids are degraded exclusively in the peroxisomes. 

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. 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

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

Under physiologic conditions, carnitine is primarily required to shuttle long-chain fatty acids across the inner mitochondrial membrane for FAO and products of peroxisomal /1-oxidation to the mitochondria for further metabolism in the citric acid cycle [40, 43]. Acylcarnitines are formed by conjugating acyl-CoA moieties to carnitine, which in the case of activated long-chain fatty acids is accomplished by CPT type I (CPT-I) [8, 44]. The acyl-group of the activated fatty acid (fatty acyl-CoA) is transferred by CPT-I from the sulfur atom of CoA to the hydroxyl group of carnitine (Fig. 3.2.1). Carnitine acylcarnitine translocase (CACT) then transfers the long-chain acylcarnitines across the inner mitochondrial membrane, where CPT-II reverses the action of CPT-I by the formation of acyl-CoA and release of free un-esterified carnitine. 

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. 

Table 3.4.1 Levels of very-long-chain fatty acids (VLCFA), pristanic acid and phytanic acid in the different peroxisomal disorders. AMACR 2-methyl acyl-CoA racemase, N normal, RCDP rhizomelic chondrodysplasia punctata, SCP-x sterol carrier protein, ZSDs Zellweger spectrum disorders,...

Moser AB, Kreiter N, Bezman L, Lu S, Raymond G V, Naidu S, Moser HW (1999) Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 45 100-110... 

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... 

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. 

Figure 2.7. The complex pathways and processes involved in fat catabolism in vertebrate tissues such as cardiac and skeletal muscles. FFAs arrive at the cell boundary either via VLDL or albumin-associated and enter the cell either by simple diffusion or through transporters. In the cytosol, FFAs are bound by FABPs, which increase the rate and amount of FFA that can be transferred to sites of utilization. Shorter chain FFAs are converted to acetylCoA in peroxisomes longer chain FFAs are directly transferred to mitochondria (via a complex system involving acylcarnitines) as long-chain acylCoA derivatives these enter the /6-oxidation spiral and are released as acetylCoA for entrance into the Krebs or citric acid cycle in the mitochondrial matrix. Fatty acid receptors (FARs) in the nucleus bind to fatty acid response elements (FAREs) and in turn regulate the production of enzymes in their own metabolism. (Modified from Veerkamp and Maatman, 1995.)...

In addition, most peroxisomes catalyze the oxidation of long-chain fatty acids to acetyl CoA (coenzyme A), which can be transported through the cytosol to mitochondria for use in the tricarboxylic acid cycle. 

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