Fatty acid synthetase inhibition

Funabashi H, Iwasaki S, Okuda S. A model study on the mechanism of fatty acid synthetase inhibition by antibiotic cerulenin. Tetrahedron Lett 1983 24 2673-2676. 

Is a specific Inhibitor of type II fatty acid synthetase In higher plants and . coll 12401. The acetyl-CoA ACP S-acety1-transferase Is the apparent specific site of Inhibition 12411. Another antibiotic, cerulenin (structure not shown) Inhbits -ketococy1-ACP synthetase I In bacteria, fungi, and plants, but also Is Inhibitory to other sites such as polyketide and sterol biosynthesis 1242-2441. Cerulenin and thiolactomycin Inhibited CQ14W-acetate Incorporation Into fatty acids at 150 values of 50 and 4 uM, respectively 12451. Recently cydohexanedlone herbicides have been shown to Inhibit lipid biosynthesis by Inhibition of acetyl-CoA carboxylase 12461. 

Methylmalonyl CoA inhibits the synthesis of fatty acids from acetyl CoA at concentrations of the order of those found in tissues of vitamin B12-deficient animals. It is a substrate for fatty acid synthetase, leading to the formation of branched-chain and odd-carbon fatty acids. 

When cells of H. cutirubrum were grown in the presence of [ C]acetate, over 98% of the label was incorporated into the isopranyl (phytanyl) groups of the polar lipids, and less than 0.5% was found in long-chain fatty acids [86]. Cell-free studies subsequently demonstrated the presence of a fatty acid synthetase (FAS) which is largely ( 80%) inhibited by 4M NaCl or KC1[87]. However, sufficient FAS activity remains for the formation of saturated fatty acids (14 0, 16 0, 18 0) recently found to be esterified to proteins of the red membrane but not to bacteriorhodopsin in the purple membrane of extreme halophiles nor to the polar lipids (Pugh and Kates, unpublished data). 

The observation that the fatty acid synthetase (FAS) in H. cutirubrum is strongly inhibited by high salt concentration while the mevalonate enzyme system for isoprenoid biosynthesis has an absolute requirement for high salt concentration (see section 4.1) may offer a clue to the mechanism of evolution of extreme halophiles from non-halophilic, or moderately halophilic precursors, and possibly also for the evolution of the methanogens and extreme thermophiles. The following hypothetical scenarios are offered for discussion (see ref [107] and Figs. 9, 14) ... 

Fatty acid synthetase, 183 Fatty acid transport, 215-216,12D, 777-774 Falty liver, 293 alcoholism, 250-251 choline deficiency, 3l7 Fatty streak, 360, 636 Fecal blood test, 84 Feedback inhibition, 256 Feeding center, brain, 103-104 Fenton reaction, 627.635,903 Fermentative metabolism, 159,181-182, 233-243... 

Mercury is a reactive element and its toxicity is probably due to interaction with proteins. Mercury has a particular affinity for sulphydryl groups in proteins and consequently is an inhibitor of various enzymes such as membrane ATPase, which are sulphydryl dependent. It can also react with amino, phosphoryl and carboxyl groups. Brain pyruvate metabolism is known to be inhibited by mercury, as are lactate dehydrogenase and fatty acid synthetase. The accumulation of mercury in lysosomes increases the activity of lysomal acid phosphatase which may be a cause of toxicity as lysosomal damage releases various hydrolytic enzymes into the cell, which can then cause cellular damage. Mercury accumulates in the kidney and is believed to cause uncoupling of oxidative phsophorylation in the mitochondria of the kidney cells. Thus, a number of mitochondrial enzymes are inhibited by Hg2+. These effects on the mitochondria will lead to a reduction of respiratory control in the renal cells and their functions such as solute reabsorption, will be compromised. 

Vance, D., Goldberg, I., Mitsuhashi, O., Bloch, K., Omura, S., and Nomura, S. (1972). Inhibition of fatty acid synthetases by the antibiotic cerulenin. Biochem. Biophys. Res. Commun. 48, 649-656. 

Oku H, Wongtangtintham S, Iwasaki H, Toda T. (2003) Conjugated linoleic acid (CLA) inhibits fatty acid synthetase activity in vitro. Biosci Biotechnol Biochem 67 1584-1586. 

Insulin Liver Increased glucokinase increased glucose uptake Increased glycogen synthase activity glycogen deposition Inhibited gluconeogenesis Increased malic enzyme, acetyl-CoA carboxylase, fatty acid synthetase and stearoylCoA desaturase increased lipogenesis Release of VLDL from hepatocytes... 

Fatty acid synthetase in animals may be subjected to short-term regulation by stimulation with phos-phorylated sugars such as fructose 1,6-diphosphate or by inhibition by palmitoyl-CoA (Wakil etal,y 1983). It is also certainly regulated by adaptive changes in enzyme content (cf. Wakil etaly 1983). 

The end product of the Type II fatty acid synthetase of plants is palmitoyl-ACP (Stumpf, 1980) which then serves as the substrate for the elongation system (palmitate elongase). Palmitate elongase has been studied in a number of soluble and membrane-bound subcellular fractions from plants (cf. Harwood, 1979). The enzyme is sensitive to arsenite in contrast to the Type II synthetase which is inhibited by cerulenin. These selective inhibitions seem to be related to the properties of the )8-ketoacyl-ACP synthetase. Two of these enzymes have been purified from spinach leaves (Shimakata and Stumpf, 19826). One will condense a broad range of primer units (up to C14) and is sensitive to cerulenin whereas the second is specific for palmitoyl-ACP and is inhibited by arsenite. The latter enzyme can, therefore, be regarded as a key part of the Type III synthetase, palmitate elongase. 

Fluorophenylalanine acts in a manner different from other inhibitors, since it permits protein synthesis. This difference in behavior results in incorporation into proteins (Westhead and Boyer, 1%1) that often possess decreased or altered activity (G and Millard, 1971). Further studies showed that the addition of fluorophenylalanine caused extensive inhibition of fatty acid and phenol (acetate-derived) synthesis shortly after administration (Ward and Packter, 1974), presumably after incorporation into the polypeptides comprising fatty acid synthetase. In contrast, cycloheximide halved... 

It has been reported that, like liver acetyl-CoA carboxylase, both the liver and yeast fatty acid synthetases are inhibited by low concentrations (0.5 to 5 X 10 71/) of long-chain fatty acyl-CoA derivatives, the longer-chain derivative producing greater inhibition [226,246,247]. In the case of the yeast synthetase, inhibition by long-chain acyl-CoA derivatives was competitive with respect to acetyl-CoA and NADPH. For the same reasons alluded to earlier in the discussion of the inhibition of acetyl-CoA carboxylase by fatty acyl-CoA derivatives, some caution must be exercised in interpreting the effect of these potent inhibitors (see Section V, C, 2). 

Many studies have revealed that thyroid hormones markedly affect lipid metabolism in man and in several species of animals. Concerning fatty acid biosynthesis it was demonstrated that the administration of thyroxine stimulates the incorporation of l-l c acetate into fatty acids in rats and mice (Dayton et al, I960) (Gompertz and Greenbaum, 1966) (March and Mayer, 1959). According to Gompertz and Greenbaum (1966) these observations appear to be associated with an increase of stearyl-CoA desaturase activity. Moreover Myant and Iliffe (1963) found that rats treated with thyroxine showed an inhibition of acetate incorporation, but not of malonate incorporation, into fatty acids by mitochondria free, subcellular liver preparations. Other authors have shown that the thyrotoxic state was accompanied by an increased incorporation of acetyl-CoA to fatty acid and a rise in the activity of fatty acid synthetase in rat livers (Diamant et al, 1972) (Roncari and Murthy, 1975). However, in vitro studies of fatty acid synthesis in which liver supernatant of 105,000 xg and microsomal preparations were incubated with the hormone showed that thyroxine inhibits de novo synthesis of palmitate and stimulates the desaturation reactions (Faas et al, 1972). 

Two antibiotics inhibit enzymes of the fatty-acid synthetase-complex cerulenin and thiolactomycin. 

When fatty acid synthetase was measured directly in chloroplast stromal fractions with [ C]malor y1-CoA, fluazifop caused no inhibition. However, if unlabelled acetyl-CoA was added simultaneously to ensure that primer concentrations were not limiting then fluazifop addition caused less reduction in labelling than for the addition of acetyl-CoA alone. Such a result would be expected since inhibition of acetyl-CoA carboxylase would prevent large-scale dilution of [ C]malonyl-CoA with unlabelled malonyl-CoA. 

Inhibition of fatty acid biosynthesis in chloroplasts The de novo synthesis of fatty acids proceeds in the chloroplasts (plastids) (35). The biosynthesis of total fatty acids in isolated maize chloroplasts is inhibited by sethoxydim (Table 7). The Igg-value is lower than 10 molar. Thus in grass weeds the major biochemical target appears to be the fatty acid synthetase. Sethoxydim acts in a similar way to the structurally different herbicide diclofopmethyl (36). The block of chlorophyll and carotenoid... 

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