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Peroxisomes and beta-oxidation of long-chain unsaturated carboxylic acids

Peroxisomes and beta-oxidation of long-chain unsaturated carboxylic acids

Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum 204: 33-46

Degradation of unsaturated long-chain carboxylic acids by beta-oxidation, which is a compartmentalized process occurring in both mitochondria and peroxisomes in mammalian cells, was studied using rat liver as a model tissue. Inclusion of (poly)unsaturated fatty acids in the perfusion medium resulted in an increased concentration of catalase-H2O2 complex indicating on-going peroxisomal beta-oxidation. For this to occur, an active peroxisomal delta 3, delta 2-enoyl-CoA isomerase was required for metabolism of the double bonds at odd-numbered positions in acyl-CoA. Experiments with isolated subcellular organelles from rat liver confirmed the presence of isomerase in the peroxisomes, and the enzyme was subsequently isolated with apparent homogeneity. Comparison of amino acid sequences from the enzyme with a published sequence for a bifunctional protein from rat liver identified them representing the same molecule. The peroxisomal bifunctional protein can thus act as a multifunctional hydratase-dehydrogenase-isomerase enzyme. Examination of the mitochondrial isomerase revealed that rat liver mitochondria possess two isoenzymes: a long-chain isomerase not induced by clofibrate-treatment and showing a preference for C10-C12 substrates, and a clofibrate-inducible short-chain isomerase which gave the highest catalytic activity with C6 substrates. Experiments with isolated peroxisomes and unsaturated acyl-CoAs demonstrated that the beta-oxidation of fatty acids having double bonds at even-numbered positions was dependent on 2,4-dienoyl-CoA reductase in peroxisomes, as in mitochondria. Immunocytochemical experiments using the protein A-gold labelling technique, and comparison of their physicochemical properties indicated that all the mammalian reductases purified so far are mitochondrial isoenzymes. It turned out during the isolation of 3-hydroxyacyl-CoA epimerase that there was no monofunctional epimerase at all in the rat liver. Instead, the epimerization reaction occurred via dehydration-hydration catalyzed by two distinct stereospecific hydratases, 2-enoyl-CoA hydratase 1 (the classic hydratase) and 2-enoyl-CoA hydratase 2 (a novel hydratase). The present data demonstrate that peroxisomes contain all the enzymes required for the beta-oxidation of unsaturated fatty acids and support the notion that one of the physiological functions of peroxisomal beta-oxidation is to metabolize long-chain hydrophobic carboxylic acids to shorter, more polar metabolites which are then either metabolized further in the body or excreted.

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Accession: 040949221

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PMID: 2042025

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