Krebs cycle aldol reactions

A similar aldol reaction is encountered in the Krebs cycle in the reaction of acetyl-CoA and oxaloacetic acid (see Section 15.3). This yields citric acid, and is catalysed by the enzyme citrate synthase. This intermediate provides the alternative terminology for the Krebs cycle, namely the citric acid cycle. The aldol reaction is easily rationalized, with acetyl-CoA providing an enolate anion nucleophile that adds to the carbonyl of oxaloacetic acid. We shall see later that esters and thioesters can also be converted into enolate anions (see Section 10.7). 

It should be noted that, on purely chemical grounds, acetoacetyl-CoA is the more acidic substrate in this reaction, and might be expected to act as the nucleophile rather than the third acetyl-CoA molecule. The enzyme thus achieves what is a less favourable reaction. There is a rather similar reaction in the Krebs cycle, where acetyl-CoA adds on to oxaloacetate via an aldol reaction, again with the enzymic reaction employing the less acidic substrate as the nucleophile (see Box 10.4). 

It is appropriate here to look at the structure of oxaloacetic acid, a critical intermediate in the Krebs cycle, and to discover that it too is a P-ketoacid. In contrast to oxalosuccinic acid, it does not suffer decarboxylation in this enzyme-mediated cycle, but is used as the electrophile for an aldol reaction with acetyl-CoA (see Box 10.4). 

The reaction catalysed by citrate synthase in the Krebs cycle (see Section 15.3) is primarily an aldol reaction, but the subsequent step, hydrolysis of a thioester linkage, is also catalysed by the same enzyme. This is shown below. 

The Krebs cycle intermediate that reacts with acetyl-CoA is oxaloacetate, and this reacts via an aldol reaction, giving citryl-CoA. However, the enzyme citrate synthase also carries out hydrolysis of the thioester linkage, so that the product is citrate hence the terminology citric acid cycle . The hydrolysis of the thioester is actually responsible for disturbing the eqnilibrinm and driving the reaction to completion. 

Citrate is a key intermediate of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, in the central metabolism of cells. (The set of reactions of the TCA cycle will be considered in some detail in Chapter 6.) One reaction in the cycle is the combination of oxaloacetate (OAA) and the acetyl group from acetyl coenzyme A (ACCOA), in the presence of H2O, to form citrate (CIT), thiol coenzyme A (COASH), and hydrogen ion (H+). The chemical reference reaction for this aldol condensation-hydrolysis reaction catalyzed by citrate synthase is ... 

Fluoroacetonitrile condenses with carbon disulfide in an interesting aldol-type reaction (Scheme 3.14). The carbanion for ethyl fluoroacetate reacts readily with benzaldehyde in a cross-aldol reaction to give the fluorinated alcohol. a-Fluorinated carbonyl compounds are often very toxic materials because biologically they are converted into fluoroacetate, which is toxic to the Krebs cycle. Thus, extreme care is needed during the use of these compounds. 

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See also in sourсe #XX -- [ ]

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