Peroxisomal oxidation chain shortening

Peroxisomes are probably also the main site of dicarboxylic acid oxidation. Dicarboxylic acids are formed from mono-carboxylic acids via initial ca-hydroxylationfollowed by oxidation of the C-OH-group to an aldehyde and finally an acid. The resulting dicarboxylic acid is activated at the ER-membrane, transported to the peroxisome and chain-shortened 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. 

As outlined herein, humans are unable to synthesise DHA from its precursor C22 5w3. The latter is therefore first converted into its C24 analogue, followed by desaturation and subsequent chain-shortening by peroxisomal /1-oxidation [7]. 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

The feeding of an EPA-free source of supplementary DHA (from algae) to human volunteers indicated a metabolic retroconversion of DHA to EPA (Conquer and Holub, 1996, 1997). Previous animal and in vitro studies in isolated rat liver cells have demonstrated that DHA can be retroconverted to EPA, and that this retroconversion is a peroxisomal function (Schlenk et al., 1969 Gronn et al., 1991). Studies in isolated rat liver cells by Schlenk et al., 1969 have also indicated that the resultant EPA can be chain-elongated to DPA (22 5n-3) for subsequent esterification into cellular lipids. An acyl-CoA oxidase has been identified as the enzyme responsible for the chain shortening of DHA in the peroxisomal beta-oxidation of PUFA in human fibroblasts (Christensen et al., 1993). The aforementioned in vivo human studies have estimated the extent of retroconversion of DHA to EPA to be approximately 10% (Conquer and Holub, 1996, 1997). 

The products of peroxisomal P-oxidation in animals are acetyl-CoA, NADH, and chain-shortened acyl-CoAs that are completely degraded in mitochondria. Chain-shortened acyl residues and acetyl groups are thought to leave peroxisomes as acylcamitines that can be formed from acyl-CoAs by peroxisomal carnitine octanoyltransferase and/or carnitine acetyltransferase [25,26]. The conversion of acyl-CoAs to acylcamitines regenerates CoA in peroxisomes as does the hydrolysis of acyl-CoAs by thioesterases. The recycling of cofactors in peroxisomes and the transport of substrates, cofactors, and metabolites across the peroxisomal membrane are aspects of p-oxidation that remain to be investigated. 

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a component of the human diet that is derived from phytol, a constituent of chlorophyll, is not degraded by p-oxidation because its 3-methyl group interferes with this process. Instead, phytanic acid is chain-shortened by a-oxidation in peroxisomes as outlined in Fig. 7 [28]. Activation... 

A small proportion of our diet consists of very-long-chain fatty acids (20 or more carbons) or branched-chain fatty acids arising from degradative products of chlorophyll. Very-long-chain fatty acid synthesis also occurs within the body, especially in cells of the brain and nervous system, which incorporate them into the sphin-golipids of myelin. These fatty acids are oxidized by peroxisomal p- and a-oxidation pathways, which are essentially chain-shortening pathways. 

It has long been recognized that fatty acids may be partially degraded with the subsequent esterification of chain-shortened products. For example, in 1964, Verdino et al. (20) reported that when 4,7,10,13,16,19-22 5 was fed to rats raised on a diet devoid of fat, there was a large increase in esterified arachi-donic acid. In 1970 Stoffel, et al. (21) showed that this partial degradative reaction was associated with a mitochondrial fraction however, these smdies were carried out before the importance of peroxisomal fatty acid 3-oxidation was recognized. In 1993, Christensen et al. (22) reported that when labeled [3-14C] 7,10,13,16-22 4 and 7,10,13,16,19-22 5 were incu-... 

Williard, D.E., Kaduce, T.L., Harmon, S.D., and Specter, A.A. (1998) Conversion of Eicosapentaenoic Acid to Chain-Shortened Omega-3 Fatty Acid Metabolites by Peroxisomal Oxidation, J. Lipid Res. 39,978-986. 

The concept of a peroxisome being a closed compartiment also requires transport systems for fatty acids which undergo oxidation in the peroxisome. Since oxidation of fatty acids in peroxisomes is incomplete, the peroxisome must also have systems to allow export of chain-shortened fatty acids. Recent evidence notably in yeast suggests that... 

The presence of a cytosolic p-oxidation system has also been described. This system was found capable of only limited chain shortening, preferred long chain acyl-CoA esters as substrate, and was less efficient than that of the mitochondrial p-oxidation system (Fiecchi et a/., 1973 Galli-Kienie et a/., 1976). The possibility that the cytosolic p-oxidation system was derived from the peroxisomes, during n vitro manipulations, appears likely (Osumi and Hashimoto, 1979). 

It should be mentioned that the heavy investment in research on rapeseed not only yielded valuable information about the crop itself but also produced a body of scientific information which greatly helped in the understanding of fat metabolism and interspecies differences in metabolic pathways. The role of the chain shortening process and peroxisomal oxidation was made clearer by studies on docosenoic acid metabolism. Valuable information was obtained from experiments which dealt with the effects of erucic acid on adrenal gland activity and prostaglandin biosynthesis. Some excellent research was done also on the effect of erucic acid on cardiac mitochondrial respiratory activity. Moreover, some interesting theories were... 

Figure 1. Metabolic steps involved in converting ALA (18 3n-3) to DHA (22 6n-3). CE, chain-elongation reaction. CS, chain-shortening reaction (peroxisomal oxidation).

The enzymes in peroxisomes do not attack shorter-chain fatty acids the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both further oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2). 

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