Fatty acid synthesis, inhibitors

Fatty acid synthesis inhibitor, by inhibition of acetyl COA carboxylase (Assase)... 

Modulation of epidermal hpid biosynthesis has been reported to boost dmg delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum corneum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-dermal delivery of lidocaine or caffeine. Alteration of barrier function was produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-fiirancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (33). 

Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in long-chain fatty acid biosynthesis (see Chapter 7.11). The overall reaction is catalyzed in two sequential reactions (Scheme 3). First, the biotin carboxylase domain catalyzes the ATP-dependent carboxylation of biotin (which is attached to a carrier protein) using bicarbonate as a CO2 donor. In the second reaction, the carboxyl group is transferred from biotin to acetyl-CoA to form malonyl-CoA. In mammals, both reactions are catalyzed by a single protein, but in Escherichia coli and other bacteria, the activity is catalyzed by two separate proteins, a biotin carboxylase and a carboxytransferase. Due to its role in fatty acid synthesis, inhibitors of the overall ACC reaction are proposed to be useful as antiobesity drugs in mammals as well as novel antibiotics against bacteria. 

Since one of the metabolic changes associated with some types of obesity in human beings and rodents is increased fatty acid synthesis, inhibitors of lipogenesis are sought as antiobesity agents. This area has been reviewed recently. ... 

When cells are grown on non-aliphatic substrates, such as glucose, fructose, acetate, or glycerol, these are converted to appropriate precursors that can be incorporated into poly(3HAMCL)s via fatty acid synthesis. The resulting PHAs have a monomer composition that is similar to that seen after growth on alkanes, often with 3-hydroxydecanoic acid as the major monomer. ( -Oxidation does not seem to play a role in the conversion of these substrates into poly(3HAMCL) since the addition of a -oxidation inhibitor did not affect the monomer composition [47]. 

Inhibitors of Bacterial Fatty Acid Synthesis as Potential Antibacterial Agents... 

Isoniazid (Fab inhibitor) Fatty Acid Synthesis Inhibition... 

Malonyl CoA, an indicator that fatty acid synthesis is active in the cytoplasm, is an inhibitor of CPT-I. 

One enzyme regulated by AMPK is acetyl-CoA carboxylase, which produces malonyl-CoA, the first intermediate committed to fatty acid synthesis. Malonyl-CoA is a powerful inhibitor of the enzyme carnitine acyl-transferase I, which starts the process of ]3 oxidation by transporting fatty acids into the mitochondrion (see Fig. 17-6). By phosphorylating and inactivating acetyl-CoA carboxylase, AMPK inhibits fatty acid synthesis while relieving the inhibition (by malonyl-CoA) of )3 oxidation (Fig. 23-37). 

The regulated step in fatty acid synthesis (acetyl CoA - malonyl CoA) is catalyzed by acetyl CoA carboxylase, which requires biotin. Citrate is the allosteric activator, and long-chain fatty acyl CoA is the inhibitor. The enzyme can also be activated in the presence of insulin and inactivated in the presence of epinephrine or glucagon. 

Similarly, factors that stimulate acetyl-CoA carboxylase, the first enzyme in the pathway for fatty acid synthesis, also discourage fatty acid catabolism. This dual effect occurs because the first enzyme in the pathway leads to the formation of malonyl-CoA, which is a potent inhibitor of carnitine acyltransferase I. This inhibition prevents the transport of fatty acids into the mitochondrion, thereby, preventing fatty acid breakdown. 

S Omura. The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev 40 681-697, 1976. 

Rose DP, Connolly JM (1990), Effects of fatty acids and inhibitors of eicosanoid synthesis on the growth of a human breast cancer cell line in culture, Cancer Res. 50 7139-7144. 

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. 

The discovery of the statin mevalonic acid synthesis inhibitors focused new attention on control of blood lipid levels as a measure to stave off heart disease. A number of compounds have been found that treat elevated lipid levels by other diverse mechanisms. The phosphonic acid derivative ibrolipim (9) is believed to lower those levels by accelerating fatty acid oxidation. The phosphoms-containing starting material 7 can in principle be obtained by the Arbuzov reaction of a protected from of p-bromomethylbenzoic acid (6) with triethyl phosphate. Removal of the protecting group and conversion of the acid to an acyl chloride then affords 7. Condensation of this intermediate with substituted aniline 8 leads to the hypolipidemic agent (9). ... 

Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones under solvent free microwave conditions using an activated arylmalonate <06TL2395>. Reacting the desired substituted aniline with di-(2,4,6-trichlorophenyl)-2-phenyl-malonate at 250 °C with microwave irradiation for 15 min resulted in a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones in good yields. They also demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors <06BMCL4620>. Kumar et al. have reported a variation of the Friedlander quinoline synthesis. They highlight the use of CeClj THjO as a reusable catalyst in the reaction of 2-... 

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... 

Harwood HJ, Jr., Petras SF, Shelly LD, et al. Isozyme-nonselective N-substituted bipi-peridylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. JBiol Chem. 2003 278(39) 37099-37111. 

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