Carbon reverse cyclative cleavage

The final step in the /3-oxidation cycle is the cleavage of the /3-ketoacyI-CoA. This reaction, catalyzed by thiolase (also known as j8-ketothiolase), involves the attack of a cysteine thiolate from the enzyme on the /3-carbonyI carbon, followed by cleavage to give the etiolate of acetyl-CoA and an enzyme-thioester intermediate (Figure 24.17). Subsequent attack by the thiol group of a second CoA and departure of the cysteine thiolate yields a new (shorter) acyl-CoA. If the reaction in Figure 24.17 is read in reverse, it is easy to see that it is a Claisen condensation—an attack of the etiolate anion of acetyl-CoA on a thioester. Despite the formation of a second thioester, this reaction has a very favorable A).q, and it drives the three previous reactions of /3-oxidation. 

Fats are metabolized down to a thioester called acetyl Co A. Acetyl Co A enters the citric acid cycle and eventually is converted to two molecules of carbon dioxide. The cleavage step in metabolizing long-chain fatty acids is the reverse of the Claisen reaction of the previous section. A thiol group attached to the enzyme is the nucleophile for general base-catalyzed addition, starting the reverse Claisen. 

There follows cleavage of acetyl-CoA from the end of the chain via a reverse Claisen reaction (see Box 10.15). This requires use of a molecule of coenzyme A as nucleophile, with the loss of the enolate anion of acetyl-CoA as leaving group. The net result is production of a new fatty acyl-CoA that is two carbons shorter than the original, and a molecule of acetyl-CoA that can be metabolized via the Krebs cycle. 

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