Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Oxidative Degradation of Amino Acids. The Urea Cycle
Ten amino acids are converted into acetyl-CoA as a result of degradation.

The carbon skeletons of ten Amino Acids are degraded to acetyl-CoA, which enters The Citric Acid Cycle directly. Five of these ten amino acids are broken down to acetyl-CoA via Pyruvate, whereas the other five are first converted to acetoacetyl-CoA, which is subsequently cleaved to acetyl-CoA (Fig. 19-4). The degradation of Alanine, Cysteine, Glycine, Serine, and Threonine proceeds via pyruvate (Fig. 19-5). Alanine is converted to pyruvate directly in a Transamination reaction with α-ketoglutarate. The four-carbon amino acid threonine is cleaved to yield the two-carbon amino acid glycine, which can undergo further METABOLISM via two distinct pathways. In one of these, glycine is first converted to serine (a three-carbon amino acid) through the enzymatic addition of a hydroxymethyl group, carried by the coenzyme tetrahydrofolate (Fig. 19-6). As we noted earlier (Section 10.10), tetrahydrofolate Functions as a carrier of one-carbon groups, such as methyl, formyl, hydroxymethyl, and formimino groups (Fig. 19-6). However, the major pathway of Glycine Catabolism proceeds via another reaction that also requires tetrahydrofolate. In this reaction, glycine undergoes oxidative Cleavage to CO₂, NH₄, and a methylene group (—CH₂—) that attaches to tetrahydrofolate. The reaction is readily reversible and is catalyzed by glycine synthase:

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Fig. 19-5. Pathways leading from threonine, glycine, serine, cysteine, and alanine to acetyl-CoA via pyruvate.

In this catabolic pathway, the two carbon atoms of glycine do not enter The Citric Acid cycle. One of them is released as CO₂, and the second is used to form the methylene group of N⁵N¹⁰-methylenetetrahydrofolate (Fig. 19-6), which serves as a methylene donor in several biosynthetic reactions.

Fragments of the carbon skeletons of phenylalanine, Tyrosine, Lysine, Tryptophan, and leucine are converted into acetoacetyl-CoA, which is subsequently transformed into acetyl-CoA (Fig. 19-7).

Two Catabolic pathways in this group deserve special attention. The pathway leading from tryptophan to acetyl-CoA is the most complex in the Amino Acid Catabolism of animal Tissues, involving 13 steps. Some intermediates of tryptophan catabolism serve as precursors in The Biosynthesis of other vital Biomolecules, such as the neurohormone serotonin or the vitamin nicotinic acid (Fig. 19-8). Thus, The pathway of tryptophan catabolism branches at several points, making it possible to generate a variety of other products from a single precursor, tryptophan.

The second fascinating pathway is the one leading from phenylalanine (Fig. 19-9). Phenylalanine and its oxidation product tyrosine are broken down into two fragments, both of which can enter the citric acid cycle, albeit at different levels. Four of the nine carbon atoms of Phenylalanine and Tyrosine yield free acetoacetate, which is then converted to acetyl-CoA (Fig. 19-7). The second four-carbon fragment of tyrosine and phenylalanine is converted into fumarate, an intermediate of the citric acid cycle (see below). Thus, eight of the nine carbon atoms of these amino acids enter the citric acid cycle; the ninth atom is released as CO₂. Phenylalanine (after hydroxylation, i.e., via tyrosine) also ultimately serves as a precursor for the thyroid hormone thyroxine and two Hormones produced by The adrenal medulla—epinephrine and norepinephrine (Chapter 25).

Fig. 19-6. A. Tetrahydrofolate (FH₄). The part of the molecule involved in carrying the one-carbon group is highlighted on a red Background. B. N⁵,N¹⁰-methylenetetrahydrofolate, formed in the glycine synthase reaction. The methylene group is highlighted on a red background.

Fig. 19-7. Pathways leading from lysine, tryptophan, phenylalanine, tyrosine, and leucine to acetyl-CoA via acetoacetyl-CoA.

Fig. 19-8. Tryptophan and some important products of its metabolic transformations.

Fig. 19-9. Normal pathway for The conversion of phenylalanine and tyrosine to acetoacetyl-CoA and fumaric acid. In phenylketonuria, The activity of the first enzyme in this pathway is impaired.