P-oxidation inhibition

See for example (a) Pospisil, J. and Klemchuk, P. P., Oxidation Inhibition in Organic Materials, Vol II, CRC Press, New York, 1990 (b) Rabek, J. F Polymer Photodegradation, Mechanisms and Experimental Methods, Chapman Hall, London, 1995 (c) Wypych, G., Handbook of Material Weathering, 2nd Edn, ChemTec Publishing, Ontario, Canada, 1995. 

P.R. Green, J. Kemper, L. Schechtman, L. Guo, M. Satkowski, S. Fiedler, A. Steinbuchel, and B.H.A. Rehm, Formation of Short Chain Length/Medium Chaiin Length Polyhydroxycilkanoate Copolymers by Fatty Acid p-Oxidation Inhibited Ralstonia eutropha. Biomacromolecules 3 208-213,2002. 

PospfSil, J, and Klemchuk, P., Oxidation Inhibition in Organic Materials, CRC Press, Boca Raton, Florida, 1990. 

Figure 2. Mechanism of PDH. The three different subunits of the PDH complex in the mitochondrial matrix (E, pyruvate decarboxylase E2, dihydrolipoamide acyltrans-ferase Ej, dihydrolipoamide dehydrogenase) catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2. E, decarboxylates pyruvate and transfers the acetyl-group to lipoamide. Lipoamide is linked to the group of a lysine residue to E2 to form a flexible chain which rotates between the active sites of E, E2, and E3. E2 then transfers the acetyl-group from lipoamide to CoASH leaving the lipoamide in the reduced form. This in turn is oxidized by E3, which is an NAD-dependent (low potential) flavoprotein, completing the catalytic cycle. PDH activity is controlled in two ways by product inhibition by NADH and acetyl-CoA formed from pyruvate (or by P-oxidation), and by inactivation by phosphorylation of Ej by a specific ATP-de-pendent protein kinase associated with the complex, or activation by dephosphorylation by a specific phosphoprotein phosphatase. The phosphatase is activated by increases in the concentration of Ca in the matrix. The combination of insulin with its cell surface receptor activates PDH by activating the phosphatase by an unknown mechanism.

P Klemchuk, J Pospisil. Oxidation Inhibition of Organic Materials, vols 1 and 2. Boca Raton CRC Press, 1990. 

KeUey, E. E., Wagner, B. A., Buettner, G. R., and Bums, C. P., 1999, Nitric oxide inhibits iron-induced Upid peroxidation in HL-60 cells. Arch. Biochem. Biophys. 370 97-104. 

O DormeU, V. B., Chumley, P. H., Hogg, N., Bloodsworth, A., Darley-Usmar, V. M., and Freeman, B. A., 1997, Nitric oxide inhibition of Upid peroxidation kinetics of reaction with lipid peroxyl radicals and comparison with alpha-tocopherol, Biochemistry 36 15216-15223. 

Sevanian, A., Shen, L., and Ursini, P., 2000, Inhibition of LDL oxidation and oxidized LDL-induced cytotoxicity by dihydropyridine calcium antagonists, Pbami. Res. 17 999-1006. 

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of p oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down p oxidation (Fig. 13-5). 

The major hormone-sensitive control point for the mobilization of fat and the p-oxidation pathway is the effect of phosphorylation on the activity of the hormone-sensitive lipase of the adipose tissue. The major direct control point for p oxidation is the inhibition of carnitine acyl-... 

Carnitine acjdtransferase-l is inhibited by malonyl CoA from fetty add synthesis and thereby prevents newly synthesized fetty adds from entering the mitochondria. Insulin indirecdy inhibits P-oxidation by activating acetyl CoA carboxylase (fetty add synthesis) and increasing the malonyl CoA concentration in the cytoplasm. Glucagon reverses this process. 

Hepatocytes were isolated from male Fischer 344 rats and from three human liver (liver transplantation donors). Treatment with mono(2-ethylhexyl) phthalate induced P-oxidation activity, replicative DNA synthesis and inhibited apoptosis induced by transforming growth factor P (TGFP) in cultured rat but not human hepatocytes (Hasmall et al., 1999). 

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. 

Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting. As a result of excessive lipolysis in adipose tis sue, the liver is flooded with fatty acids (see p. 328). The rate of for mation of acetyl CoA by p-oxidation of these fatty acids exceeds the capacity of the liver to oxidize it to C02 and H20. As a result, acetyl CoA accumulates and leads to activation of pyruvate carboxylase. [Note Acetyl CoA inhibits pyruvate dehydrogenase (see p. 108). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle.]... 

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. 

Gugumus F (1990) In Pospisil J, Klemchuk P (eds) Oxidation inhibition of organic ma-terials-2. CRC, Boca Raton, p 29... 

Wang, D., Yu, X., and Brecher, P. 1999. Nitric oxide inhibits angiotensin II-induced activation of the calcium-sensitive tyrosine kinase proline-rich tyrosine kinase 2 without affecting epidermal growth factor receptor transactivation. J. Biol. Chem. 274 24342-24348. 

---