Citric acid prochirality

A large number of biological reactions involve prochiral compounds. One of the steps in the citric acid cycle by which food is metabolized, for instance, is... 

Elucidating the stereochemistry of reaction at prochirality centers is a powerful method for studying detailed mechanisms in biochemical reactions. As just one example, the conversion of citrate to (ds)-aconitate in the citric acid cycle has been shown to occur with loss of a pro-R hydrogen, implying that the reaction takes place by an anti elimination mechanism. That is, the OH and H groups leave from opposite sides of the molecule. 

A. G. Ogston in 1948 explained the dilemma of how an enzyme can enan-tiospecifically produce a chiral product from a prochiral molecule such as citric acid or 2-aminomalonic acid. He pointed out two requirements three-point contact at three active sites (a, b, and c ) and catalytic dissimilarity between the two active sites (a and b ) associated with the pro-R and pro-5 groups (a and b) of the prochiral molecule as shown in Fig. 3.2. 

The prochirality concept is not necessarily an expression of a precursor-product relationship because there exist stereoselective reactions at pro-chiral elements that do not generate elements of chirality. An illustration of this is the reversible enzymatic dehydration of citric to cu-aconitic acid. In this process two prochiral centers of citric acid disappear and we obtain an achiral line of stereoisomerism that physically coincides with a prochiral plane of prostereoisomerism. 

It should be mentioned that the central carbon atom of citric acid becomes chiral when the two peripheral carboxy groups are substituted differently (examples will be found below). For enzyme reactions it is a prochirality center. This has been shown for vibrioferrin (58) and staphyloferrin B (59). 

Citric acid has three prochiral centres The Krebs cycle is a process involved in the metabolic degradation of carbohydrate (see Section 15.3). It is also called the ciU ic acid cycle, because citric acid was one of the first intermediates identified. Once formed, citric acid is modified by the enzyme aconitase through the intermediate... 

Exercise 20-23 Citric acid is prochiral. Nonetheless, if one were to introduce acetyl... 

The prochiral center in citric acid is attached to two CH2COOH groups. The configurational question can, therefore, be phrased as the question, does acetyl-CoA contribute the pro-R or pro-S CH2COOH groups To provide an answer proved more difficult than for the relatively simple CabH2H cases so far discussed. The proof requires knowledge about several other enzymes and, as well, information about the chirality of compounds related to shikimic acid. 

Dehydroquinase is an enzyme in the pathway responsible for forming aromatic amino acids from acyclic precursors [116]. It is part of a 5-enzyme complex in Neurospora crassa which exhibits the property of co-ordinate activation by the first substrate [117]. The enzyme Aerobacter aerogenes was used by Hanson and Rose [118] to determine the absolute stereochemical course of citric acid biosynthesis. These workers also demonstrated that the elimination of water proceeds in a SYN manner with the prochiral R-proton removed followed by elimination of hydroxide. This was in contrast to the commonly observed anti-elimination of water from most... 

Citric acid played a major role in the development of the concept of prochirality. Its two CH2CO2H chains groups behave differently in a key step of the Krebs cycle, so differently that some wondered whether citric acid itself were really involved. Alexander Ogston (Oxford) provided the answer in 1948 when he pointed out that the two CH2CO2H groups are differentiated when citric acid interacts with the chiral environment of an enzyme. 

You might note that C2 of glycerol is a prochiral center with two identical arms, a situation similar to that of citrate in the citric acid cycle (Section 22.4). As is typical for enzyme-catalyzed reactions, the phosphorylation of glycerol is selective. Only the pro-R arm undergoes reaction, although this can t be predicted in advance. 

Sometimes, also the notation H Cit is used for it in the literature, when the hydrogen atom from hydroxyl group is involved in complexation reactions. There are no asymmetric carbon atoms in citric acid or in its anions, i.e. they are optically inactive. However, it is possible to make them asymmetrical by substitution of one of the hydrogen atoms in the methylene groups by another atom or group (the central carbon atom is prochiral). 

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