Fatty acids, activation metabolism

Acyl-CoAs are the activated intermediates of fatty acid metabolism formed by the condensation of fatty acids with Coenzyme A. 

The 3-ketothiolase has been purified and investigated from several poly(3HB)-synthesizing bacteria including Azotobacter beijerinckii [10], Ral-stonia eutropha [11], Zoogloea ramigera [12], Rhodococcus ruber [13], and Methylobacterium rhodesianum [14]. In R. eutropha the 3-ketothiolase occurs in two different forms, called A and B, which have different substrate specificities [11,15]. In the thiolytic reaction, enzyme A is only active with C4 and C5 3-ketoacyl-CoA whereas the substrate spectrum of enzyme B is much broader, since it is active with C4 to C10 substrates [11]. Enzyme A seems to be the main biosynthetic enzyme acting in the poly(3HB) synthesis pathway, while enzyme B should rather have a catabolic function in fatty-acid metabolism. However, in vitro studies with reconstituted purified enzyme systems have demonstrated that enzyme B can also contribute to poly(3HB) synthesis [15]. 

These agents activate PPAR-y a nuclear transcription factor important in fat cell differentiation and fatty acid metabolism. PPAR-yagonists enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be present in significant quantities for these actions to occur. 

Chenoweth believes that an explanation of the above results may lie in the reactions occurring before the entrance of fatty acid metabolites into the citric acid cycle. Activated acetate, i.e. acetyl coenzyme A (AcCoA) is the end-product of fatty acid metabolism prior to its condensation with oxalacetate to form citrate. Possibly fluoro-fatty acids behave like non-fluorinated fatty acids. The end-product before the oxalacetate condensation could be the same for all three fluorinated inhibitors, viz. fluoroacetyl coenzyme A (FAcCoA). Fluorocitrate could then be formed by the condensation of oxalacetate with FAcCoA, thereby blocking the citric acid cycle. The specificity of antagonisms must therefore occur before entrance of the metabolites into the citric acid cycle. 

The free fatty acid needs activating before it can be metabolized. This is achieved by conversion into... 

Cinnamyl anthranilate has the characteristic effects of a peroxisome proliferator on mouse liver, increasing the activity of peroxisomal fatty acid-metabolizing enzymes and microsomal CYP4A and increasing hepatocellular proliferation. These effects are mediated by the intact ester, and were not seen after administration of the hydrolysis products, cinnamyl alcohol and anthranilic acid. The corresponding effects on rat liver were very much weaker. No relevant data from humans were available. 

In tissues such as of the liver, mitochondrial activities such as fatty acid metabolism are compromised, and the liver eventually fails with potentially fatal consequences. 

Ethanoic acid is activated for biosynthesis by combination with the thiol, coenzyme A (CoASH, Figure 18-7) to give the thioester, ethanoyl (acetyl) coenzyme A (CH3COSC0A). You may recall that the metabolic degradation of fats also involves this coenzyme (Section 18-8F) and it is tempting to assume that fatty acid biosynthesis is simply the reverse of fatty acid metabolism to CH3COSCoA. However, this is not quite the case. In fact, it is a general observation in biochemistry that primary metabolites are synthesized by different routes from those by which they are metabolized (for example, compare the pathways of carbon in photosynthesis and metabolism of carbohydrates, Sections 20-9,10). 

Certain bioflavonoids may play a preventive role against cardiovascular diseases. Some citrus and other bioflavonoids have been demonstrated to reduce serum cholesterol levels and to affect fatty acid metabolism (70,71,72). The strong antiadhesive action on red cells and platelets of highly methoxylated flavones such as nobiletin, which also demonstrates antithrombogenic activity (73), indicates an important role in blood rheology and tissue perfusion. The antiadhesive action may indicate a preventive role in atherosclerosis since there is evidence that reduced perfusion of the vascular wall may interact with serum lipids to promote atherogenesis (74). 

Blockade of fatty acid metabolism in the membrane, thus impairing diacyglycerocapacity to stimulate protein kinase C activity... 

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