Acetyl-CoA carboxylase activation

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Knafo, L., Chessex, P., Rouleau,T., and Lavoie, J-C. (2005), Association between hydrogen peroxide-dependent byproducts of ascorbic acid and increased hepatic acetyl-CoA carboxylase activity, Clin. Chem., 51,1462-1471. 

Additional information <1> (<1> two other cAMP-independent kinases found, that phosphorylate but do not effect acetyl-CoA carboxylase kinase activity [6] <1> phosphorylation by cAMP-dependent protein kinase has the same effect on acetyl-CoA carboxylase activity then phosphorylation with acetyl-CoA carboxylase kinase-2 [6,7] <1> cAMP-dependent protein kinase identified, that phosphorylates and inactivates acetyl-CoA carboxylase in vitro, but appears not to be involved in regulation in vivo [8]) [6-8]... 

Ottey, K.A. Munday, M.R. Calvert, D.T. Clegg, R.A. Effect of anoxia on acetyl-CoA carboxylase activity possible role for an AMP-activated protein kinase. Biochem. Soc. Trans., 17, 350-351 (1989)... 

Figure 4. Effect of haloxyfop methyl ester (A), haloxyfop free acid (O), and tralkoxydim ( ) on acetyl CoA carboxylase activity from maize.

Acetyl CoA carboxylase activity Stimulation Galactolipid sulfotransferase Inhibition... 

Fatty acid biosynthesis is regulated largely by hormonal mechanisms (Figure 18.34). Acetyl-CoA carboxylase, the first enzyme in the pathway, is an important regulatory enzyme for the entire pathway. Fatty acid biosynthesis is inactivated in two ways through control of acetyl-CoA carboxylase activity ... 

Fig. 4.4. The control of acetyl-CoA carboxylase activity by allosteric effectors and by phosphOTylation.

Acetyl-CoA carboxylase activity can be altered by interaction with citrate and other tricarboxylic acids. Much attention has been paid to hepatocyte systems where compounds such as glucagon or dibutyryl cyclic AMP lower cytosolic citrate levels which cause a lowered acetyl-CoA carboxylase activity (Lane et al, 1979). The latter is also inhibited by raised fatty acyl-CoA concentrations which cause depolymerization of the mammalian carboxylase. Information is available concerning inhibitor specificity and interactions with other subcellular compounds (cf. Wakil et al, 1983). The mammalian acetyl-CoA carboxylase has also been reported to undergo covalent modification through phosphorylation/ dephosphorylation. Such regulation may involve the simultaneous presence of Co A (Yeh et aL, 1981). Various kinase and phosphatase enzymes which may be important in the modification of the mammalian acetyl-CoA carboxylase have been purified (cf. Wakil etal., 1983). 

It has been shown that the carboxylation of acetyl-CoA is effectivelyf the rate-determining reaction of fatty acid synthesis in animal tissues [94] and therefore has regulatory potential. In the absence of tricarboxylic acid activator, acetyl-CoA carboxylase activity is lower by nearly two orders of magnitude than in the fully activated state where its catalytic capacity is nearly kinetically matched to those of the citrate cleavage enzyme and fatty acid synthetase [76,77,94,150]. Therefore, changes in the level of tricarboxylic acid effector presumably could control the rate of the carboxylase reaction, and thus regulate fatty acid synthesis. 

Insulin deficiency impairs several steps in lipogenesis as a result of decreased penetration of glucose and utilization in glycolytic pathway with reduced formation of a-glycerophosphate, decreased pyruvate dehydrogenase and acetyl CoA carboxylase activities with reduced fatty acid chain initiation, decreased fatty acid synthetase activity. 

This reaction is stimulated by adding the tricarboxylic acid cycle intermediates, and citric acid is particularly effective in that respect. Thus, is interesting that in starved diabetic rats acetyl CoA carboxylase activity is reduced. Furthermore, Frohman and his associate have found that the concentration of the Krebs cycle intermediate is greatly reduced in liver of diabetic rats [141]. 

Feeding a fat-free diet to rats results not only in the fatty acid changes cited previously but also in increased synthesis of palmitic acid in rats injected intratesticularly with C-acetate or in slices of testes incubated with C-acetate. There was relatively less incorporated into the polyenes in the tissue from the deficient rats (Whorton Coniglio, 1977). It was observed that there was no effect on fatty acid synthetase or on microsomal elongation enzymes, but there was an increase in the acetyl CoA carboxylase activity of testes of the fat-deficient rats. 

Operation of the FAS system involves an enzyme-catalyzed cycle of condensation, reduction, dehydration and a second reduction (Figure 3.2), and is dependent upon the supply of a carbon source and energy provision in the forms of ATP, NADH and NADPH. The extreme importance of acetyl-CoA carboxylase activity to the functioning of FAS may be deduced from the observed close proximity of each system to each other in plastidic membranes of maturing rape seed (Slabas and Smith, 1988). 

Secor J. and Cseke C., 1988. Inhibition of acetyl-CoA carboxylase activity by haloxyfop and tralkoxydim. Plant Physiol. 86, 10-12. 

Plant acetyl-CoA carboxylase is localised in the chloroplasts of leaf tissues Its activity, which is low in the dark, is raised considerably by the illumination of leaves. On illumination it is known that stromal concentrations of ATP and Mg increase while that of ADP decreases . From kinetic data it can be estimated that nucleotide and Mg " changes would each result in a doubling of acetyl-CoA carboxylase activity. This would be in line with the observation of Eastwell and Stumpf that wheatgerm acetyl-CoA carboxylase can be tightly controlled in vitro through its requirement for ATP and its inhibition by ADP and AMP. 

The above results imply that acetyl-CoA carboxylase may be the rate-limiting enzyme for de novo fatty acid synthesis. Indeed, in seeds the level of acetyl-CoA carboxylase activity correlate with the accumulation of lipid in developing castor bean and rape seeds. However, unlike the mammalian enzyme, plant acetyl-CoA carboxylase does not seem to be consistently stimulated by tricarboxylic acids c.f. . ... 

Acetyl-CoA carboxylase activity (on the basis of protein or fresh weight) was similar In embryogenlcally Incompetent cells and embryogenlc cell clusters In maintenance medium (Table 1). However, the activity of this enzyme, per mg protein, was 2- to 15-fold higher in cells and embryos from an Induced culture. More Importantly, acetyl-CoA carboxylase activity Increases as the embryos develop from embryogenlc cell clusters to form globular, heart and torpedo embryos. These data are consistent with the requirement for higher acetyl-CoA carboxylase activity in embryos for cuticle biosynthesis. 

Culture fractions Acetyl-CoA Carboxylase Activity (nmol/mln) ... 

Davis MS, Solbiati J, Cronan JE Jr (2000) Overproduction of acetyl-CoA carboxylase activity increases the rate of fatty acid biosynthesis in Escherichia coli. J Biol Chem 275 (37) 28593-28598. doi 10.1074/jbc.M004756200... 

It is well-known that light stimulates lipid synthesis in photosynthetic tissues generally. This effect can be followed conveniently through the incorporation of radioactivity from C-acetate. Some of the stimulation is probably due to increased cofactor supply [see 3]. However, there may be other controls on carbon flux to fatty acids and their incorporation into acyl lipids. Attention has focused particularly on acetyl-CoA carboxylase activity. Since this enzyme catalyses the first committed step in lipid synthesis and is known to be subject to careful regulation in other organisms [10] then such a concept is perfectly reasonable. Experiments with the maize acetyl-CoA carboxylase identified a number of factors which would change in the stroma during active... 

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