Acetyl-CoA carboxylase inhibition

Inhibitor Long-chain fatty acyl CoA (inhibits acetyl CoA carboxylase) Malonyl CoA (inhibits carnitine palmitoyltransferase)... 

Kudo, N., Gillespie, J. G., Kung, L., Witters, L. A., Schulz, R., Qanachan, A. S., and Lopaschuk, G. D. 1996. Characterization of 5 AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1301 67-75. 

As stated earlier, the hormones glucagon and epinephrine, present under conditions of fasting and exercise, will stimulate the release of fatty acids from triacylglycerols in fat cells, which will be released into the blood, and probably from muscle cells, where they will be used immediately as fuel. These same hormones will inhibit fatty acid synthesis by inhibiting acetyl CoA carboxylase. Although the exact mechanism by which these... 

Acetyl CoA is converted to malonyl CoA and into fatty acids as described previously. The enzyme that carries out the first committed step for fatty-acid synthesis, acetyl CoA carboxylase, is finely controlled both allosterically and covalently. This enzyme can occur in a monomeric inactive form or a polymeric active form. One factor that affects this is citrate, which stimulates the polymeric or active form of acetyl CoA carboxylase. Thus, citrate plays an important role in lipogenesis as (1) a source of cytosolic acetyl CoA, (2) an allosteric positive effector of acetyl CoA carboxylase, and (3) a provider of oxaloacetate in the cytosol, which can allow transhydrogenation from NADH to NADPH. An allosteric inhibitor of acetyl CoA carboxylase that causes dissociation to the monomeric form is fatty-acyl CoA. Thus, if exogenous fatty acids are available, there is little reason to synthesize more fatty acids. Fatty-acyl CoA in the cytosol decreases malonyl CoA formation by inhibiting acetyl CoA carboxylase. 

When large amounts of exogenous fatty acid enter the liver, how can they be transferred into the mitochondrion, for beta oxidation, with malonyl CoA inhibition This dichotomy is overcome because fatty-acyl CoAs inhibit acetyl CoA carboxylase and the malonyl CoA present proceeds onto fatty acids. When the malonyl CoA is converted to fatty acid, the level of malonyl CoA drops and is not restored. Thus, the inhibition of acyl carnitine transferase 1 is removed and fatty-acid oxidation can proceed. 

Relationship between fattyacid synthesis and degradation. This diagram shows that malonyl CoA inhibits CPTI and thereby b-oxidation, avoiding the oxidation of newly synthesized fatty acids. Fatty-acyl CoA inhibits acetyl CoA carboxylase and thereby fatty-acid synthesis. When fatty-acyl CoAs are converted to triacylglycerols or phospholipids, they are effectively removed and will no longer be inhibitory. 

Because malonyl CoA is a substrate for fatty acid synthase, competition from methyl-malonyl CoA could cause a decrease in the rate of palmitoyl CoA synthesis in the cytosol, which could in turn lead to an increase in the concentration of acetyl CoA because palmitoyl CoA inhibits acetyl CoA carboxylase. In addition, high levels of methylmalonyl CoA could interfere with transport of long-chain fatty acyl chains into mitochondria by inhibiting carnitine acyltransferase, as does malonyl CoA. Thus, both the synthesis and the oxidation of fatty acids could be inhibited by methylmalonyl CoA. 

Sethoxydim (e.g., Poast ) inhibits acetyl CoA carboxylase (ACCase) which is the first committed step in de novo fatty acid synthesis. SR corn was achieved by traditional breeding and selection for the herbicide insensitive ACCase allele and was introduced in 1996. SR corn accounted for less than 0.3% of corn acres in any one year and is no longer commercially available in field com (Fig. 6.1.4). 

Malonyl-CoA, the product of the acetyl-CoA carboxylase reaction, is substrate for the biosynthesis of fatty acids. It is also an inhibitor of carnitine palmitoyltransferase (CPT), the enzyme regulating mitochondrial fatty acid oxidation. Long-chain acyl-CoA inhibits malonyl-CoA synthesis by inhibiting acetyl-CoA carboxylase. An acute... 

Figure 11.10 Interactions between fatty acid synthesis and oxidation in liver. In the fed state malonyl-CoA levels are high. This allows rapid fatty acid synthesis and inhibits jS-oxidation by lowering carnitine acyltransferase I activity. If triacylglycerol synthesis is impaired then acyl-CoAs will feedback to inhibit acetyl-CoA carboxylase. In the fed state this does not normally happen and tri-acylglycerols are incorporated into very-low-density lipoprotein for export to extrahepatic tissues. Glucagon excess in fasting leads to a suppression of glycolysis, cessation of lipogenesis and activation of -oxidation and ketogenesis. Reproduced with permission from Annual Review of Biochemistry, 49, 1980 by Annual Reviews Inc.

Several hypolipidemic drugs (2-methyl-2-phenoxypropionate derivatives) have been found to inhibit acetyl-CoA carboxylase [240,241]. All appear to inhibit competitively with respect to acetyl-CoA and tricarboxylic acid activator and noncompetitively with respect to ATP and HCOs . These inhibitors, like malonyl-CoA and palmityl-CoA, are antagonistic to the activator in that they tend to reverse the activator-promoted aggregation of the carboxylase (see Fig. 7). Confirmation of the inhibitory effect of these drugs on lipogenesis at the carboxylase-catalyzed step in vivo would lend substantial support to the proposed regulatory role of the carboxylase. 

Fatty acyl CoA in the cytosol implies a high rate of fatty acid uptake from the bloodstream fatty acyl CoA inhibits acetyl CoA carboxylase and so reduces the rate of malonyl CoA synthesis and fatty acid synthesis. 

Malonyl-CoA, the product of the acetyl-CoA carboxylase reaction, is substrate for the biosynthesis of fatty acids. It is also an inhibitor of carnitine palmitoyltransferase (CPT), the enzyme regulating mitochondrial fatty acid oxidation. Long-chain acyl-CoA inhibits malonyl-CoA synthesis by inhibiting acetyl-CoA carboxylase. An acute decrease in malonyl-CoA at 4-6 hr has been found in animals treated with TTA. " At that time the levels of long-chain acyl-CoA was increased. A rise in cellular acyl-CoA after administration of 3-thia fatty acids could result in inhibition of the enzyme acetyl-CoA carboxylase. Reduced levels of malonyl-CoA could then relieve inhibition of CFT and the mitochondrial fatty acid oxidation would be stimulated. ... 

FLUAZIFOP, A GRASS-SPECIFIC HERBICIDE, ACTS BY INHIBITING ACETYL-CoA CARBOXYLASE... 

Figure 3.8. Structures of some aryloxyphenoxypropionates and cyclohexanediones that have been shown to inhibit acetyl-CoA carboxylase in sensitive species.

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