Oxidation of Fatty Acids:- Peroxisomes Also Carry Out β Oxidation
The mitochondrial matrix is the major site of fatty acid oxidation in animal cells, but in certain cells other compartments also contain enzymes capable of oxidizing fatty acids to acetyl-CoA, by a pathway similar to, but not identical with, that in mitochondria. In plant cells, the major site of β oxidation is not mitochondria but peroxisomes.
In peroxisomes, membrane-enclosed organelles of animal and plant cells, the intermediates for oxidation of fatty acids are coenzyme A derivatives, and the process consists of four steps, as in mitochondrial β oxidation (Fig. 17–13): (1) dehydrogenation, (2) addition of water to the resulting double bond, (3) oxidation of the β -hydroxyacyl-CoA to a ketone, and (4) thiolytic cleavage by coenzyme A. (The identical reactions also occur in glyoxysomes, as discussed below.) One difference between the peroxisomal and mitochondrial pathways is in the chemistry of the first step. In peroxisomes, the flavoprotein acyl-CoA oxidase that introduces the double bond passes electrons directly to O2, producing H2O2 (Fig. 17–13). This strong and potentially damaging oxidant is immediately cleaved to H2O and O2 by catalase. Recall that in mitochondria, the electrons removed in the first oxidation step pass through the respiratory chain to O2 to produce H2O, and this process is accompanied by ATP synthesis. In peroxisomes, the energy released in the first oxidative step of fatty acid breakdown is not conserved as ATP, but is dissipated as heat.
A second important difference between mitochondrial and peroxisomal β 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 en zymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious hu man 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 oxidize very-long-chain fatty acids, apparently for lack of a functional transporter for these fatty acids in the peroxisomal membrane. Both defects lead to accumulation in the blood of very-long-chain fatty acids, especially 26:0. XALD affects young boys before the age of 10 years, causing loss of vision, behavioral disturbances, and death within a few years.
In mammals, high concentrations of fats in the diet result in increased synthesis of the enzymes of peroxisomal oxidation in the liver. Liver peroxisomes do not contain the enzymes of the citric acid cycle and cannot catalyze the oxidation of acetyl-CoA to CO2. Instead, long-chain or branched fatty acids are catabolized to shorter-chain products, such as hexanoyl-CoA, which are exported to mitochondria and completely oxidized.
FIGURE 17–13 Comparison of β oxidation in mitochondria and in peroxisomes and glyoxysomes. The peroxisomal/glyoxysomal system differs from the mitochondrial system in two respects: (1) in the first oxidative step electrons pass directly to O2, generating H2O2, and (2) the NADH formed in the second oxidative step cannot be reoxidized in the peroxisome or glyoxysome, so reducing equivalents are exported to the cytosol, eventually entering mitochondria. The acetyl CoA produced by peroxisomes and glyoxysomes is also exported; the acetate from glyoxysomes (organelles found only in germinating seeds) serves as a biosynthetic precursor (see Fig. 17–14). Acetyl-CoA produced in mitochondria is further oxidized in the citric acid cycle.
