Fatty Acid Metabolism

Acetyl coenzyme A is a central metabolite for both the biosynthesis and catabolism of fatty acids. Although the steps in the biosynthetic and catabolic schemes are closely related, there are specific differences. The individual steps are also independent by their spatial separation in biological cells, as biosynthesis occurs in the
cytosol while catabolism takes place in the mitochondria. The evennumbered ([C 2 ] n ) common fatty acids result from the sequential two-carbon elongation of acetyl CoA by a series of enzymatic reactions utilizing one or more molecules of acetyl CoA. The two-step elongation scheme of fatty acid biosynthesis is catalyzed by either discrete enzymes catalyzing specific steps or by a large multi-enzyme complex able to catalyze all steps in the pathway.

The first step of converting acetyl CoA into the more reactive acetylacyl carrier protein (Acetyl-ACP) is catalyzed by ACP transacylase. The acetyl group is then transferred from ACP to a cysteine residue of the synthase complex. In the third step, carboxylation of acetyl CoA is catalyzed by acetyl CoA carboxylase with bicarbonate and ATP to yield malonyl CoA and ADP. In this reaction, biotin acts as a carbon dioxide carrier which transfers carbon dioxide to acetyl CoA. The malonyl group is subsequently converted through a nucleophilic acyl substitution reaction into malonyl-ACP. Thus, both acetyl and malonyl groups are bound to an ACP arm of the synthase complex. The key fifth step consists of the Claisen condensation reaction between the bound acetyl and malonyl groups to give acetoacetyl-ACP. In the sixth step, an enantioselective reduction of the ketone carbonyl group catalyzed by ß-ketothioester reductase yields ß-hydroxybutyryl-ACP, with a new chiral center in the R -configuration. Enzymatic dehydration in step 7 yields trans -crotonyl-ACP, which is converted in step 8 by NADPH-dependent reduction of the carboncarbon double bond to butyryl-ACP.

Fatty acid catabolism in the mitochondria of cells provides energy by the ß-oxidation pathway and is composed of a repetitive sequence of four enzymatic reaction steps. The fatty acid chain is cleaved from the carboxy-terminus in a stepwise fashion. The first step of the ß-oxidation pathway starts with an acyl CoA-dehydrogenasecatalyzed desaturation at C2-C3 using an FAD cofactor to yield an a,ß-unsaturated acyl-CoA. An enoyl-CoA hydratase-catalyzed syn- addition of water to the a,ß-unsaturated acyl-CoA in the second step yields 3 S -hydroxyacyl-CoA. Next, 3 S -hydroxyacyl-CoA is oxidized to the corresponding ß-ketoacyl-CoA by NAD-dependent enantioselective 3-hydroxyacyl-CoA dehydrogenases. In the final step, the ß-ketoester is cleaved to two CoA esters in a ß-ketoacylthiolase-catalyzed retro-Claisen reaction. While the common fatty acids with an even number of carbon atoms produce two molecules of acetyl-CoA in the final passage, fatty acids with an odd number of carbon atoms lead to one molecule of acetyl-CoA and one molecule of propionyl-CoA.