Acetyl-CoA enolization

A histidine deprotonates the acetyl-CoA enol, which adds to the ketone carbonyl group of oxaloacetate in an aldol-like reaction. Simultaneously, an acid N-H proton of another histidine protonates the carbonyl oxygen, producing (S)-citryl CoA. 

Step 2 of Figure 27.7 Aldol Condensation Acetoacetyl CoA next undergoes an aldol-like addition (Section 23.1) of an acetyl CoA enolate ion in a reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA synthase. The reaction again occurs... 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

For some enzymes, for example many metalloenzymes, a semiempirical QM/MM treatment is inadequate due to the limitations of the semiempirical methods. In such situations, a more sophisticated level of QM treatment (such as ab initio molecular orbital or density-functional theory) may well be required. An recent example of the application of ab initio QM/MM techniques to an enzyme mechanism is a study of acetyl-CoA enolization in citrate synthase... 

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