Glutamic acid, aspartic acid and their amides occupy an important place in the metabolism of nitrogenous compounds. We know that glutamic acid was the main entry point of ammonia into biological compounds and we will see that its metabolism is linked to that of several other amino acids; as for its amide, glutamine, it plays an important role in the storage and elimination of NH3 and contributes, to the biosynthesis of purine nucleotides.
We will note that a number of amino acids derive from aspartic acid and we already know that the latter participates in the synthesis of purine and pyrimidine nucleotides; that it is also necessary for the formation of urea.
But these two amino acids are also important from the point of view of intermediate metabolism in general; actually, their corresponding α-keto acids are intermediates of Krebs cycle and therefore constitute contact points between carbohydrate and protein metabolisms.
A. Metabolism of Glutamic Acid and Glutamin:
a) Review of Some Important Reactions:
Glutamic acid is formed from α-ketoglutaric acid, either by reducing animation, or by transamination. As observed in the foregoing, glutamic acid very often participates in transamination processes during which it parts with its amino group to permit the formation of other amino acids.
By decarboxylation it gives γ-aminobutyric acid, an inhibition mediator of synapses mainly found in the brain. It is also a constituent of glutathione, the synthesis of which we studied in connection with glycine. Besides, it is a constituent of pteroylglutamic acid or folic acid (see fig. 2-19), whose tetrahydrogenated derivative (FH4) plays a capital role in the transport of one-carbon units.
b) Metabolic Inter-Relations between Glutamic Acid, Ornithine and Proline:
As shown by figure 7-21, glutamic γ-semialdehyde (resulting from glutamic acid by reduction of its γ-carboxyl) can either cyclize itself and give proline (and hydroxyproline, but hydroxylation takes place on the proline already incorporated in proteins), or undergo a transamination which converts it into ornithine-, ornithine easily leads to arginine by the ureogenesis cycle. These reactions are reversible.
c) Metabolism of Glutamine:
Glutamine enables the storage of NH3 which is toxic for animal tissues, and it is an intermediate in the elimination of NH3; the major part of urine ammonia in mammals results from the hydrolysis of blood glutamine in the kidney.
We have seen how glutamine is formed from glutamic acid and how it yields its amidic NH2 during the synthesis of purine nucleotides, the formation of carbamyl-phosphate and the amination of UTP to CTP. It also permits the formation of osamines.
Lastly, like glycine, glutamine participates in detoxication processes, and phenyl-acetic acid for example, is excreted combined with the α-amino group of glutamine.
B. Metabolism of Aspartic Acid and Asparagine:
a) Review of Some Important Reactions:
Aspartic acid is formed by transamination from oxalo-acetic acid. It can yield its amino group by transamination to permit the formation of other amino acids and it gives back oxaloacetic acid. Oxalo-acetic acid occupies a key position, because on the one hand it is so to speak the “starting point” of the Krebs cycle, since it takes over the acetyl-coA molecules from the carbohydrates and lipids, and on the other hand, it is the starting point of neoglucogenesis (see figs. 4-34 and 4-38).
Besides, aspartic acid can also join the Krebs cycle at the level of fumaric acid by deamination. We have seen that aspartic acid is a precursor of purine nucleotides and pyrimidine nucleotides. Aspartic acid also plays an important role in ureogenesis.
Aspartic acid can undergo a decarboxylation either in α and give β-alanine (a constituent of the coenzyme A), or in β and give alanine. With NH3 and in presence of ATP, aspartic acid gives the corresponding amide, asparagine, which is an important form of reserve of ammonia in plants.
b) Amino Acids Derived from Aspartic Acid:
Aspartic acid is the precursor of threonine, isoleucine, methionine and lysine, in some organisms (for example, lysine is synthesized from aspartic acid in bacteria and some plants, while it is produced from glutamic acid, in a totally different way, in yeast and moulds), but in man these 4 amino acids are essential.
We will briefly study the broad lines of these transformations of aspartic acid (excepting the reactions leading to lysine, because they involve intermediates somewhat more complex in their structures). These transformations form a highly branched reactive chain which we will take as example to study the various possible modes of regulation in metabolic pathways presenting branches.
As shown by figure 7-22, the common trunk is very short as it comprises only 2 reactions: phosphorylation of aspartic acid on its β-carboxyl by a β-aspar- tokinase and then reduction of this compound to aspartate-β-semialdehyde. This is already the starting point of the first branch which leads to lysine by 7 reactions.
On the other hand, aspartate-β-semialdehyde can be reduced to homoserine where a second branch is found: one of the pathways leads to threonine and then isoleucine; the second leads to methionine thanks to a trans-sulphuration which we already studied in connection with the transformation methionine → cysteine indicating that it takes place in the direction cysteine → methionine only in some organisms.
Figure 7-23 is an overall diagram of the metabolism of aspartic and glutamic acids and their amides.
