Inhibition, of fatty acid

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Experiments with chloroplasts showed an apparent inhibition of fatty acid synthesis by PAN (at 72 ppm for 10 min). The result is difficult to interpret the inhibition could be attributed to inactivation of one of the enzymes of the multistep system or to oxidation of the reductant (reduced NADP, or NADPH) required in the chain elongation process. 

Cerulenin inhibits formation of polyisoprenol, probably by uncom-petitively inhibiting HMG-CoA synthetase.250 It strongly inhibited production of Rous-sarcoma virus by infected, chick-embryo cells, but an effect on the viral glycoproteins was not observed.251 Other effects of cerulenin, such as its inhibition of fatty acid synthesis, may have caused inhibition of virus production. The inhibition, by cerulenin, of secretion of proteins by bacilli has been noted for some time, but no satisfactory explanation has as yet been offered (see Ref. 252, and ref-... 

Gamble, J. Lopaschuk, G.D. Insulin inhibition of 5 -adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism, 46, 1270-1274 (1997)... 

Inhibition of fatty acid hydrolase (FAAH) - a new target for pain research ... 

When blood glucose levels drop between meals, glucagon release activatescAMP-dependent protein kinase (FKA), which phoe phorylates and inactivates ACC. The concentration of malonyl-CoA falls, the inhibition of fatty acid entry into mitochondria is relieved, and fatty acids enter the mitochondrial matrix and become the major fuel. Because glucagon also triggers the mobilization of fatty acids in adipose tissue, a supply of fatty acids begins arriving in the blood. 

The energy state of the cell dictates the relative rates of phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol biosynthesis. When energy is in short supply, the level of cAMP rises leading to inhibition of fatty acid biosynthesis (see chapter 18). This in turn decreases the supply of diacylglycerol, which limits the synthesis of phosphatidylcholine, phosphatidylethanolamine, and triacylglycerol. When sufficient diacylglycerol is pres-... 

G D Agnolo, IS Rosenfeld, J Awaya, S Omura, PR Vagelos. Inhibition of fatty acid synthesis by the antibiotic cerulenin specific inactivation of P-ketoacyl-acyl carrier protein synthase. Biochem Biophys Acta 236 155-166, 1973. 

Varvel, S. A., Wise, L. E., Niyuhire, F., Cravatt, B. F., and Lichtman, A. H. (2007). Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32, 1032-1041. 

Jhaveri, M. D., Richardson, D., Robinson, I., Garle, M. J., Patel, A., Sun, Y., Sagar, D. R., Bennett, A. J., Alexander, S. P., Kendall, D. A., Barrett, D. A., and Chapman, V. (2008). Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabi-noid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55, 85—93. 

Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/ MM) modelling. Biochem Soc Trans 37(Pt 2) 363-367... 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

Caspary F, Elliott G, Nave BT, Verzaal P, Rohrbach M, Das PK, Nagelkerken L, Nieland JD. A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by Etomoxir. Brit J Dermatol 2005 153 937-44. 

Quizalofop or 2-[4-[(6-chloro-2-quinoxalinyl)oxyphenoxy] propanoic acid Aryloxyphenoxy acid Inhibition of fatty acid synthesis selective for grass weeds Potatoes, soy beans, cotton, flax 11-5... 

Neurological complications also are associated with vitamin B-12 deficiency and result from a progressive demyelination of nerve cells. The demyelination is thought to result from the increase in methylmalonyl-CoA that result from vitamin B-12 deficiency. Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis as well as being able to substitute for malonyl-CoA in any fatty acid biosynthesis that may occur. Since the myelin sheath is in continual flux the methylmalonyl-CoA-induced inhibition of fatty acid synthesis results in the eventual destruction of the sheath. The incorporation methylmalonyl-CoA into fatty acid biosynthesis results in branched-chain fatty acids being produced that may severely alter the architecture of the normal membrane structure of nerve cells... 

Harmon CM, Luce P, Beth AH, Abumrad NA (1991) Labeling of adipocyte membranes by sulfo-N-succinimidyl derivatives of long-chain fatty acids inhibition of fatty acid transport. J Membr Biol 121 261-268... 

Fowler CJ, Tiger G, Lopez-Rodriguez ML, Viso A, Ortega-Gutierrez S, Ramos JA (2003) Inhibition of fatty acid amidohydrolase, the enzyme responsible for the metabolism of the endocannabinoid anandamide, by analogues of arachidonoyl-serotonin. J Enzyme Inhib Med Chem 18 225-231... 

Holt S, NUsson J, Omeir R, Tiger G, Fowler CJ (2001) Effects of pH on the inhibition of fatty acid amidohydrolase by ibuprofen. Br J Pharmacol 133 513-520... 

Nakamura MT, Cho HP, Clarke SD. Regulation of hepatic delta-6 desaturase expression and its role in the polyunsaturated fatty acid inhibition of fatty acid synthase gene expression in mice. J Nutr 2000 30 1561-1565. 

The myocardium preferentially oxidizes fatty acids to fulfill the energy requirements necessary for efficient pump function. However, during myocardial ischemia, decreased cellular oxygen content, in conjunction with reduction of the redox potential, result in the inhibition of fatty acid P-oxidation leading to the accumulation of fatty acyl metabolites, including acylCoA and acylcamitine (cf, Neely and Morgan, 1974). 

The clinical efficacy of fatty acid oxidation inhibitors has not yet been proven. Some beneficial effects have been noted in insulin-dependent diabetics, but no controlled clinical trials in non-insulin-dependent diabetics have been reported. Although the inhibition of fatty acid oxidation causes hypoglycaemia in the fasted state, it is unclear whether these compounds will be effective in an individual with normal eating habits. The safety and efficacy of this class of compounds can be determined only by further studies. 

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