Mitochondrial P-oxidation

Eaton S, Bartlett K, Pourfarzam M Mammalian mitochondrial P-oxidation. BiochemJ 1996 320 345. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Figure 7.15 The interaction between valproate and the mitochondrial p-oxidation system. Dark arrows denote depletion. Filled in circle is the carnitine transporter. 2,4, VPA 2,4, diene-VPA CoA ester. This reactive metabolite damages the enzyme enoyl CoA hydratase and the mitochondrial membranes and depletes GSH, as indicated.

Unsaturated fatty acids. Mitochondrial P oxidation of such unsaturated acids as the A9-oleic acid begins with removal of two molecules of acetyl-CoA to form a A5-acyl-CoA. However, further metabolism is slow. Two pathways have been identified (Eq. 17-l).26 29b The first step for both is a normal dehydrogenation to a 2-fraus-5-czs-dienoyl-CoA. In pathway I this intermediate reacts slowly by the normal p oxidation sequence to form a 3-czs-enoyl-CoA intermediate which must then be acted upon by an auxiliary enzyme, a ds-AMra s-A2-enoyl-CoA isomerase (Eq. 17-1, step c), before P oxidation can continue. 

Mitochondrial P oxidation of fatty acids is the principal source of energy for the heart. Consequently, inherited defects of fatty acid oxidation or of carnitine-assisted transport often appear as serious heart disease (inherited cardiomyopathy). These may involve heart failure, pulmonary edema, or sudden infant death. 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

How does peroxisomal P-oxidation differ from mitochondrial P-oxidation ... 

In animal cells, fatty acids are degraded both in mitochondria and peroxisomes, whereas in lower eukaryotes, P-oxidation is confined to peroxisomes. Mitochondrial P-oxidation provides energy for oxidative phosphorylation and generates acetyl-CoA for ketogenesis in liver. The oxidation of fatty acids with odd numbers of carbon atoms also yields propi-onyl-CoA that is metabolized to succinate. 

Eaton, S. 2002. Control of mitochondrial P-oxidation flux. Prog. Lipid Res. 41 197-239. 

Unsaturated fatty acids. Mitochondrial p oxidation of such unsaturated acids as the A -oleic acid begins with removal of two molecules of acetyl-CoA to form a A -acyl-CoA. However, further metabolism is slow. Two pathways have been identified (Eq. 

Fig. 23.3. Major metabolic routes for long-chain fatty acyl Co As. Fatty acids are activated to acyl CoA compounds for degradation in mitochondrial P-oxidation, or incorporation into triacylglycerols or membrane lipids. When P-oxidation is blocked through an inherited enzyme deficiency, or metabolic regulation, excess fatty acids are diverted into tri-acylglycerol synthesis.

Very-long-chain fatty acids of 24 to 26 carbons are oxidized exclusively in peroxisomes by a sequence of reactions similar to mitochondrial p-oxidation in that they generate acetyl CoA and NADH. However, the peroxisomal oxidation of straight-chain fatty acids stops when the chain reaches 4 to 6 carbons in length. Some of the long-chain fatty acids also may be oxidized by this route. 

Tamoxifen. The antiestrogen, tamoxifen, is a cationic amphiphilic drug which is electrophoretically transported into the mitochondrial matrix where it reaches high concentrations that directly inhibit both mitochondrial p-oxidation and mitochondrial respiration, and also deplete mtDNA in mice, as mentioned above (Larosche et al. 2007). 

Glucocorticoids. Glucocorticoids impair mitochondrial p-oxidation by inhibiting acyl-CoA dehydrogenases (Letteron et al. 1997), and can cause steatosis and even steatohepatitis in humans (Itoh et al. 1977). 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

Calcium hopantenate. The administration of the pantothenic acid antagonist, calcium hopantenate (also called calcium homopantothenate), can decrease CoA and inhibit mitochondrial p-oxidation, and it has caused several cases of Reye s-like syndrome in Japan (Noda et al. 1988). 

Mitochondrial cytopathies affect mitochondrial respiration, which may secondarily inhibit p-oxidation, as explained above. Mitochondrial cytopathies may therefore be revealed during the administration of drugs that have mitochondrial effects. Thus, the administration of valproate, which inhibits mitochondrial p-oxidation and pyruvate-supported respiration, may reveal a previously latent mitochondrial cytopathy (Chabrol et al. 1994 Lam et al. 1997 Krahenbiihl et al. 2000). For the same reasons, valproate administration can also reveal an inborn p-oxidation defect (Nj0lstad et al. 1997 Kottlors et al. 2001). 

Freneaux E, Fromenty B, Berson A, Labbe G, Degott C, Letteron P, Larrey D, Pessayre D (1990) Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial P-oxidation of fatty acids. J Pharmacol Exp Ther 255 529-535... 

Fromenty B, Pessayre D (1995) Inhibition of mitochondrial P-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther 67 101-154... 

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