Biochemistry - The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Biosynthesis of Monomers
Keto acid chains. The elongation process

Let us recall that The conversion of glyoxylate to Pyruvate (see Fig. 11-6) proceeds via a sequence of reactions reminiscent of the conversion of oxaloacetate to ß-ketoglutarate in The Tricarboxylic Acid Cycle (Fig. 9-2). Both of these reaction sequences exemplify the general principle of ß-keto acid chain elongation, which is widely utilized in Biosynthesis. For instance, this principle is applied in the synthesis of leucine and Lysine. The reaction sequence, presented in generalized form in Fig. 11-7, comprises four stages: 1) Condensation of an a-keto acid with an acetyl group; 2) isomerization proceeding via dehydration and rehydration (such as aconitase in the tricarboxylic acid cycle); 3) dehydrogenation; and 4) ß-decarboxylation. In many instances, stages 3 and 4 occur concurrently and are catalyzed by a single enzyme. Note that the hydroxy acid formed as an intermediate (Fig. 11-7) must undergo isomerization because the hydroxyl group is attached to a quaternary carbon lacking a hydrogen atom. During this isomerization process, the hydroxyl group must shift to the adjacent carbon atom prior to oxidation to a ketone. In the case of glyoxylate, however, isomerization is unnecessary since the R group here is hydrogen.

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FIG. 11-7. The keto acid chain elongation process.

It might be argued that the tricarboxylic acid cycle reaction converting oxaloacetate to ketoglutarate does not strictly follow the pathway illustrated in Fig. 11-7. Indeed, the CO₂ molecule released during the decarboxylation step originates not from the moiety derived from the acetyl group, but from the portion formed from oxaloacetate. Nevertheless, the net result is identical in both cases. Furthermore, it is now established that two Enzymes catalyze citrate synthesis while exhibiting distinct stereospecificities (Chapter 7, Section K,2,e). Therefore, it is entirely possible that the primordial biosynthetic pathway strictly adhered to the reaction sequence shown in Fig. 11-7.

The lower part of Fig. 11-7 illustrates the sequence in which certain Stages of the a-keto acid elongation process take place. As shown, this sequence of reactions enables glyoxylate (the product of the acetyl-CoA-Glyoxylate cycle) to be successively extended into pyruvate, oxaloacetate, a-ketoglutarate, and the precursor of lysine.