Acyl-S-CoA

All cases discussed in this section involve the reaction between an amine and an acyl group to yield an amide. The high-energy cofactor required is in most cases an acyl-coenzyme A derivative (acyl-S-CoA) where the acyl moiety is bound by a thioester linkage. 

Ethyl acetates of fatty acids, mainly ethyl caproate and caprylate, are produced by yeast during alcoholic fermentation. They are synthesized from forms of the acids activated by the coenzyme A (HS-CoA), acyl-S-CoA. Acetyl-S-CoA, from pyruvic acid, may be involved in a Claisen reaction with malonyl-S-CoA, producing a new acyl-S-CoA with two additional carbon atoms (Figure 2.9). Acetyl-S-CoA thus produces butyryl-S-CoA, then hexanyl-S-CoA, etc. Specific enzymes then catalyze the alcoholysis of acyl-S-CoA into ethyl acetates of fatty acids. At the same time, the coenzyme A is regenerated. 

By 1960 it was clear that acetyl CoA provided its two carbon atoms to the to and co—1 positions of palmitate. All the other carbon atoms entered via malonyl CoA (Wakil and Ganguly, 1959 Brady et al. 1960). It was also known that 3H-NADPH donated tritium to palmitate. It had been shown too that fatty acid synthesis was very susceptible to inhibition by p-hydroxy mercuribenzoate, TV-ethyl maleimide, and other thiol reagents. If the system was pre-incubated with acetyl CoA, considerable protection was afforded against the mercuribenzoate. In 1961 Lynen and Tada suggested tightly bound acyl-S-enzyme complexes were intermediates in fatty acid synthesis in the yeast system. The malonyl-S-enzyme complex condensed with acyl CoA and the B-keto-product reduced by NADPH, dehydrated, and reduced again to yield the (acyl+2C)-S-enzyme complex. Lynen and Tada thought the reactions were catalyzed by a multifunctional enzyme system. 

The S-CoA derivative then acylates the amino group of the particular amino acid in an analogous way to the acetylation of amine groups described above, yielding a peptide conjugate. This is catalyzed by an amino acid N-acyltransferase, which is located in the mitochondria. Two such enzymes have been purified, each using a different group of CoA derivatives. 

Amino Acid Conjugation. In the second type of acylation reaction, exogenous carboxylic acids are activated to form S-CoA derivative in a reaction involving ATP and CoA. These CoA derivatives then acylate the amino group of a variety of amino acids. Glycine and glutamate appear to be the most common acceptor of amino acids in mammals in other organisms, other amino acids are involved. These include ornithine in reptiles and birds and taurine in fish. 

R—COOH) forming an acyl-CoA thioester (R—CO—S— CoA) as the metabolic intermediate and as a cofactor. The reaction requires ATP and is catalyzed by various acyl-CoA synthetases also known as acyl-CoA Ugases (Table 32.5) of overlapping substrate specificity. The acyl-CoA conjugates thus formed are seldom excreted, but they can be isolated and characterized relatively easily in in vitro studies. In the present context, the interest of acyl-CoA conjugates is then-further transformation by a considerable variety of path-ways22.37,52 54 summarized in Table 32.6. 

Ketoacyl-S-CoA + CoASH <=> Acyl-CoA + Acetyl-CoA (catalyzed by Ketothiolase)(Figure 18.16). 

The most common reactions of acylation are in fact acetylations of xenobiotics containing a primary amino group. The cofactor of acetylation is acetylcoenzyme A (acetyl-S-CoA), the reaction being catalysed by a variety of A-acetyltransferases. Arylamine Af-acetyltransferases (NAT-1 and -2) are the most important enzyme, but aromatic-hydroxylamine O-acetyltransferase and N-hydroxyarylamine >-acetyltransferase are also involved in the acetylation of some aromatic amines and hydroxyl-amines. 

Isoleucine can give its amino group to a-ketoglutarate in a transamination reaction and then be oxidatively decarboxylated and dehydrogenated to form the corresponding (a,(3)-unsaturated acyl-CoA derivative. Further reactions (see the figure on p. 424) then are identical to fatty acid oxidation until the carbon skeleton is split into acetyl-S-CoA and propionyl-S-CoA. The three subsequent steps for the conversion of the (odd-chain) propionyl-S-CoA to succinyl-S-CoA have been discussed for the oxidation of odd-chain fatty acids (see Chapter 22). 

---