Peroxisomal oxidation of fatty acids

Lazarow P (1981) Assay of peroxisomal -oxidation of fatty acids. Methods in Enzymology 72 315-319... 

In pantothenic acid-deficient rats, tissue CoA is depleted, affecting mainly the peroxisomal oxidation of fatty acids, which is mainly concerned with detoxication mitochondrial /3 -oxidation, which is an essential energy-yielding pathway, is spared to a great extent (Youssef et al., 1997). However, relatively moderate deficiency in animals results in increased plasma triacylglycerol and nonesterifled fatty acids, suggesting some impairment of lipid metabolism (Wittwer et al., 1990). 

Most fatty acids are saturated and even-numbered. They are broken down via p-oxidation (see p.l64). In addition, there are special pathways involving degradation of unsaturated fatty acids (A), degradation of fatty acids with an odd number of C atoms (B), a and ro oxidation of fatty acids, and degradation in peroxisomes. 

As well as cytochrome P-450, other enzymes are induced by peroxisome proliferators such as clofibrate. Thus enzymes involved in the 3-oxidation of fatty acids are increased and other structural proteins are also increased (see chap. 7). This is, therefore, another example of a pleiotropic effect, similar to the induction via the AhR discussed above. 

Recent research using NMR has revealed novel noninvasive biomarkers for peroxisomal proliferation. These are two breakdown products of NAD detectable in plasma by HPLC. These reflect the increased demand and production of NAD for oxidation metabolism such as (3-oxidation of fatty acids. This biomarker will be useful in studies in humans, especially clinical trials of more potent lipid-lowering drugs. 

Peroxisomal proliferators chemicals that change the number and characteristics of peroxisomes (intracellular organelles which carry out oxidation of fatty acids). These chemicals also may cause liver cancer and induce a number of enzymes. 

In peroxisomes, membrane-enclosed organelles of animal and plant cells, the intermediates for /3 oxidation of fatty acids are coenzyme A derivatives, and the process consists of four steps, as in mitochondrial /3 oxidation (Fig. 17-13) (1) dehydrogenation, (2) addition of water to the resulting double bond, (3) oxidation of the /3-hydroxyacyl-CoA to a ketone, and (4) thiolytic cleavage by coenzyme A (The identical reactions also occur in glyoxysomes, as discussed below.)... 

Kunau, W.H., Dommes, V, Schulz, H. (1995) /3-Oxidation of fatty acids in mitochondria, peroxisomes, and bacteria a century of continued progress. Prog. Lipid Res. 34, 267-342. 

Yonssef JA, Song WO, and Badr MZ (1997) Mitochondrial, bnt not peroxisomal, beta-oxidation of fatty acids is conserved in coenzyme A-deflcient rat liver. Molecular and Cellular Biochemistry 175,37-42. 

This hepatomegaly is correlated to PPARa activation of acyl-CoA oxidase (AOX), the first enzyme of peroxisomal /3-oxidation of fatty acids and a gene with a PPRE in its promoter region14. In addition, hepatic mitochondrial /3-oxidation and microsomal w-oxidation of fatty acids are increased, as a direct result of PPARa activation of mRNA of specific enzymes associated with these pathways (carnitine palmitoyl transferase I and cytochrome P4504A, respectively). Activation of fatty acid oxidation by these three pathways would lead to enhanced fatty acid oxidation, given the appropriate substrate. PPARa has also been shown to enhance delivery of fatty acids to the oxidizing systems (Fig. 3). 

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... 

Peroxisomes have /J-oxidation enzymes that are specific for long- chain fatty acids, whereas mitochondria possess enzymes that are specific for short and moderate chain length fatty acids. In addidon, the first reaction in the peroxisomal pathway is catalyzed by a different enzyme than the mitochondrial pathway. The FADH, produced in the first peroxisomal reaction donates its electrons to O, directly, (forming H202) instead of UQ as in mitochondria. The processes are similar in that acetyl-CoA is derived from the oxidation of fatty acids. 

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