Biochemistry, Vol. 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Amino Acids and Nucleotides
A common biosynthetic pathway leads to glutamate, glutamine, and proline

First, we will examine the Biosynthesis of nonessential Amino Acids, i.e., those amino acids that can be synthesized by humans, white rats, and other mammals. In most cases, the carbon Skeleton of a nonessential amino acid is derived from a corresponding a-keto acid, which ultimately originates from an intermediate of The Citric Acid Cycle. Amino groups are usually supplied by glutamate via Transamination reactions (Section 19.1) catalyzed by transaminases, which employ Pyridoxal phosphate as a prosthetic group (Section 10.8).

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Fig. 22-1. Biosynthesis of three related amino acids: glutamate, glutamine, and Proline. The pathway converting glutamate to proline is shown in Fig. 22-2.

The biosynthetic pathways leading to the three related amino acids—glutamate, glutamine, and proline (Fig. 22-1)—are straightforward and appear to be identical across all life forms. Glutamate is formed from ammonia and a-ketoglutarate (an intermediate of The Citric Acid cycle) through the action of L-Glutamate dehydrogenase. NADPH serves as the source of reducing equivalents in the glutamate dehydrogenase reaction.

This reaction is of fundamental importance for The biosynthesis of all amino acids because glutamate acts as an amino group donor in transamination reactions during the Synthesis of Other amino acids. L-glutamate dehydrogenase is localized in the mitochondrial matrix.

Glutamine is formed from glutamate in a reaction catalyzed by Glutamine Synthetase.

Recall that this two-step reaction proceeds via a glutamyl-5-phosphate intermediate (Section 19.12).

Fig. 22-2. Biosynthesis of L-proline. All five carbon atoms of proline are derived from glutamic acid. Proline acts as an allosteric inhibitor of The enzyme catalyzing the first reaction in the proline biosynthesis pathway. This negative feedback regulation is indicated here by a red arrow, and the inhibited reaction is marked with a red crossbar.

This is also one of the pivotal reactions in Amino acid METABOLISM because it represents the primary pathway for converting free ammonia—which is known to be toxic—into nontoxic glutamine for transport in the bloodstream (Section 19.12). Glutamine synthetase is an allosteric enzyme. In E. coli and other prokaryotes, the catalytic activity of glutamine synthetase is regulated by several metabolites, as discussed below.

Proline, which is a cyclic derivative of glutamate, is synthesized as shown in Fig. 22-2. First, glutamate is reduced to the corresponding y-semialdehyde, followed by ring closure coupled with further reduction, ultimately yielding proline.