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Mouse

Normal 1 1

Obese mutant 4 3

Mouse

Normal 1 1

Obese mutant 4 3

Acetyl-CoA carboxylase-« mRNAs occur in a variety of forms as a result of the functioning of two independent promoters (PI and PII) and differential splicing of the primary transcripts. The different ACC mRNAs are expressed tissue specifically, depending on the physiological state of the tissue. The generation of multiple mRNAs provides an extra dimension to control of ACC activity. For example, it is known that the 5'-untranslated regions are involved in the regulation of translation of specific mRNA species. The promoters PI and PII respond to particular physiological stimuli. Thus PII, which is constitutively expressed, contains an elaborate array of cis-elements (including those for insulin, cAMP and glucose) that affect its activity.

2.2.8.2 Acetyl-CoA carboxylase regulation in other organisms

The ACC from yeast is also inhibited by acyl-CoAs, but unlike the animal enzyme, is unaffected by citrate. In some mutant strains an activation by fructose-l,6-bisphosphate has been demonstrated. Like the mammalian carboxylase, the enzyme from yeast is also regulated by changes in amount. An interesting example of the role of fatty acyl-CoA in mediating the rate of synthesis of acetyl-CoA car-boxylase has been demonstrated in fatty acid mutants of C. lipolytics These mutants contained no apparent fatty acyl-CoA synthetase and hence, were unable to grow on exogenous fatty acids, when their own fatty acid synthesis was blocked by inhibitors. However, further examination showed that the mutants did have one type of fatty acyl-CoA synthetase (called II) in common with normal cells but lacked fatty acyl-CoA synthetase I which was needed for membrane lipid synthesis. Fatty acyl-CoA synthetase II is used for activating fatty acids destined for P-oxidation. Thus, these two acyl-CoA synthetases are responsible for generating two pools of acyl-CoAs in different parts of the cell. The acyl-CoAs formed by acyl-CoA synthetase I are in the cytosol and these cause repression of ACC (Fig. 2.26).

Regulation of E. coli ACC on the other hand, seems to be by a completely different system. In this bacterium (and others such as Pseudomonas citronellolis) highly phosphorylated guanosine nucleotides seem to be important. These compounds (guanine-5'-diphosphate-3'-diphosphate, ppGpp and guanine-5'-triphosphate-3'-dipho-

sphate, pppGpp) act by inhibiting the carboxyl-transferase partial reaction.

In plants, ACC has been identified as an important site for flux control during fatty acid synthesis in leaves. Fatty acid synthesis in such tissues is very much stimulated by light (about 20-fold) and this increase was accompanied by changes in the pool sizes of acetyl and malonyl thioesters consistent with large alterations of acetyl-CoA carboxylase activity. This was confirmed by the use of specific inhibitors that showed that most of the regulation of carbon into fatty acids and lipids was by ACC. However, the mechanism of control is poorly understood. In light stimulation experiments the activation of ACC may be secondary to stromal solute changes (ATP, ADP, Mg2+ and pH) that accompany photosynthesis. On the other hand, feedback control may play a role in some tissues although classical effectors such as citrate or acyl-CoAs do not seem to be effective at physiologically relevant concentrations in plants.

2.2.8.3 Regulation of fatty acid synthase

In the same way as the actual levels of ACC protein can be changed in animals under dietary influence so can that of fatty acid synthase (FAS, Table 2.ll). Up to 20-fold differences have been observed in the levels of, for example, liver fatty acid synthase between starved and carbohydrate re-fed animals. Alterations in both synthesis and degradation of the enzyme seem to be involved.

It should be noted that dietary factors that affect FAS levels do not affect all tissues equally. While the liver is highly influenced by such regulation, the FAS of brain is unaffected. This is just as well for it would be extremely disadvantageous for a young animal to have its brain development influenced dramatically by its day-to-day nutritional state!

While re-feeding a high carbohydrate diet causes an increase in hepatic FAS protein levels, fat feeding reduces them. However, the effects of fat are complex with polyunsaturated fatty acids being particularly effective.

In addition, a number of hormones including insulin, glucocorticoids, glucagon, theophylline and oestradiol have also been found to produce

Yeast Biochemistry
Fig. 2.26 Interaction of acyl-CoA pools with fatty acid metabolism in the hydrocarbon-utilizing yeast Candida lipolytics Reproduced with kind permission of Dr. S. Numa (1981) and Elsevier Trends Journals from Trends in Biochemical Science, Fig. 2, p. 115.
Table 2.H Effect of nutritional state or hormones on liver fatty acid synthase levels

Cause increase

Cause decrease

Re-feeding

Starvation

Insulin

Alloxan-diabetes

ß-Oestradiol

Glucagona

Hydrocortisone

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