Biosynthesis of Amino Acids:- α-Ketoglutarate Gives Rise to Glutamate, Glutamine, Proline, and Arginine
We have already described the biosynthesis of glutamate and glutamine. Proline is a cyclized derivative of glutamate (Fig. 1). In the first step of proline synthesis, ATP reacts with the γ-carboxyl group of glutamate to form an acyl phosphate, which is reduced by NADPH or NADH to glutamate γ-semialdehyde. This intermediate undergoes rapid spontaneous cyclization and is then reduced further to yield proline. Arginine is synthesized from glutamate via or nithine and the urea cycle in animals (Chapter 18). In principle, ornithine could also be synthesized from glutamate γ-semialdehyde by transamination, but the spontaneous cyclization of the semialdehyde in the proline pathway precludes a sufficient supply of this intermedi ate for ornithine synthesis. Bacteria have a de novo biosynthetic pathway for ornithine (and thus arginine) that parallels some steps of the proline pathway but in cludes two additional steps that avoid the problem of the spontaneous cyclization of glutamate γ-semialdehyde (Fig. 1). In the first step, the γ-amino group of glutamate is blocked by an acetylation requiring acetyl-CoA;
then, after the transamination step, the acetyl group is removed to yield ornithine. The pathways to proline and arginine are somewhat different in mammals. Proline can be synthesized by the pathway shown in Figure 22–10, but it is also formed from arginine obtained from dietary or tissue protein. Arginase, a urea cycle enzyme, converts arginine to ornithine and urea . The ornithine is converted to glutamate -semialdehyde by the enzyme ornithine δ -aminotransferase . The semi aldehyde cyclizes to Δ1-pyrroline-5-carboxylate, which is then converted to proline (Fig. 1). The pathway for arginine synthesis shown in Figure 1 is absent in mammals. When arginine from dietary intake or protein turnover is insufficient for protein synthesis, the ornithine δ-aminotransferase reaction operates in the direction of ornithine formation. Ornithine is then con verted to citrulline and arginine in the urea cycle.
FIGURE 1 Biosynthesis of proline and arginine from glutamate in bacteria. All five carbon atoms of proline arise from glutamate. In many organisms, glutamate dehydrogenase is unusual in that it uses either NADH or NADPH as a cofactor. The same may be true of other enzymes in these pathways. The -semialdehyde in the proline path way undergoes a rapid, reversible cyclization to Δ1-pyrroline-5 carboxylate (P5C), with the equilibrium favoring P5C formation. Cyclization is averted in the ornithine/arginine pathway by acetylation of the α-amino group of glutamate in the first step and removal of the acetyl group after the transamination. Although some bacteria lack arginase and thus the complete urea cycle, they can synthesize argi nine from ornithine in steps that parallel the mammalian urea cycle, with citrulline and argininosuccinate as intermediates . Here, and in subsequent figures in this chapter, the reaction arrows indicate the linear path to the final products, without considering the reversibility of individual steps. For example, the second step of the pathway leading to arginine, catalyzed by N-acetylglutamate dehydrogenase, is chemically similar to the glyceraldehyde 3-phosphate dehydrogenase reaction in glycolysis and is readily reversible.
