We now turn to the fates of the carbon skeletons of amino acids after the removal of the α-amino group. The strategy of amino acid degradation is to transform the carbon skeletons into major metabolic intermediates that can be converted into glucose or oxidized by the citric acid cycle. The conversion pathways range from extremely simple to quite complex. The carbon skeletons of the diverse set of 20 fundamental amino acids are funneled into only seven molecules: pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate. The conversion of 20 amino acid carbon skeletons into only seven molecules illustrates the remarkable economy of metabolic conversions, as well as the importance of certain metabolites.

Amino acids that are degraded to acetyl CoA or acetoacetyl CoA are termed ketogenic amino acids because they can give rise to ketone bodies or fatty acids but cannot be used to synthesize glucose. Recall that mammals lack a pathway for the net synthesis of glucose from acetyl CoA or acetoacetyl CoA. Amino acids that are degraded to pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate are termed glucogenic amino acids. Oxaloacetate, generated from pyruvate and other citric acid cycle intermediates, and pyruvate can be converted into phosphoenolpyruvate and then into glucose through gluconeogenesis.

Of the basic set of 20 amino acids, only leucine and lysine are solely ketogenic (Figure 30.5). Threonine, isoleucine, phenylalanine, tryptophan, and tyrosine are both ketogenic and glucogenic. Some of their carbon atoms emerge in acetyl CoA or acetoacetyl CoA, whereas others appear in potential precursors of glucose. The other 14 amino acids are classified as solely glucogenic. We will identify the degradation pathways by the entry point into metabolism. Additionally, because some degradation pathways are quite complex, they will be presented in outline form, with only some of the key intermediates highlighted.

Pyruvate is the entry point of the three-carbon amino acids—alanine, serine, and cysteine—into the metabolic mainstream (Figure 30.6). As stated earlier in the chapter, the transamination of alanine directly yields pyruvate:

Another simple reaction in the degradation of amino acids is the deamination of serine to pyruvate by serine dehydratase:

The conversion of cysteine into pyruvate is more complex. The conversion can take place through several pathways, with cysteine’s sulfur atom emerging in H₂S, SCN^–, or SO₃^2–.

The carbon atoms of three other amino acids also can be converted into pyruvate. Glycine can be converted into serine by the enzymatic addition of a hydroxymethyl group, or it can be cleaved to yield CO₂, NH₄⁺, and the activated one-carbon unit tetrahydrofolate (Chapter 31). Threonine gives rise to 2-amino-3-ketobutyrate, which yields pyruvate or acetyl CoA. Three carbon atoms of tryptophan can emerge in alanine, which can be converted into pyruvate.

Aspartate and asparagine are converted into oxaloacetate, a citric acid cycle intermediate. Aspartate, a four-carbon amino acid, is directly transaminated to oxaloacetate:

Asparagine is hydrolyzed by asparaginase to NH₄⁺ and aspartate, which is then transaminated, as shown in the preceding reaction.

Recall that aspartate can also be converted into fumarate by the urea cycle. Fumarate is also a point of entry for half the carbon atoms of tyrosine and phenylalanine, as will be discussed shortly.

The carbon skeletons of several five-carbon amino acids enter the citric acid cycle at α-ketoglutarate. These amino acids are first converted into glutamate, which, as described earlier in the chapter, is then oxidatively deaminated by glutamate dehydrogenase to yield α-ketoglutarate (Figure 30.7).

Histidine is converted into glutamate through the intermediate 4-imidazolone 5-propionate (Figure 30.8). The amide bond in the ring of this intermediate is hydrolyzed to the N-formimino derivative of glutamate, which is then converted into glutamate by transfer of its formimino group to tetrahydrofolate.

Glutamine is hydrolyzed to glutamate and NH₄⁺ by glutaminase. Proline and arginine are each converted into glutamate γ-semialdehyde, which is then oxidized to glutamate (Figure 30.9).

Succinyl CoA is a point of entry for some of the carbon atoms of methionine, isoleucine, and valine. Propionyl CoA and then methylmalonyl CoA are intermediates in the breakdown of these three nonpolar amino acids (Figure 30.10). This pathway from propionyl CoA to succinyl CoA is also used in the oxidation of odd-chain fatty acids. Because the conversion of methylmalonyl CoA into succinyl CoA is a vitamin B₁₂–dependent reaction, accumulation of methylmalonic acid is a clinical indicator of possible vitamin B₁₂ deficiency.

The degradation of the branched-chain amino acids (leucine, isoleucine, and valine) employs reactions that we have already encountered in the citric acid cycle and fatty acid oxidation. Leucine is transaminated to the corresponding α-ketoacid, α-ketoisocaproate. This α-ketoacid is oxidatively decarboxylated to isovaleryl CoA by the branched-chain α-ketoacid dehydrogenase complex. The α-ketoacids of valine and isoleucine, the other two branched-chain aliphatic amino acids, as well as α-ketobutyrate derived from methionine, also are substrates. The oxidative decarboxylation of these α-ketoacids is analogous to that of pyruvate to acetyl CoA and of α-ketoglutarate to succinyl CoA.

The isovaleryl CoA derived from leucine is dehydrogenated to yield β-methylcrotonyl CoA. The hydrogen acceptor is FAD, as in the analogous reaction in fatty acid oxidation. β-Methylglutaconyl CoA is then formed by the carboxylation of β-methylcrotonyl CoA at the expense of the hydrolysis of a molecule of ATP in a reaction similar to that of pyruvate carboxylase and acetyl CoA carboxylase:

β-Methylglutaconyl CoA is hydrated to form 3-hydroxy-3-methylglutaryl CoA, which is cleaved into acetyl CoA and acetoacetate. This reaction has already been discussed in regard to the formation of ketone bodies from fatty acids.

The degradative pathways of valine and isoleucine resemble that of leucine. After transamination and oxidative decarboxylation to yield a coenzyme A derivative, the subsequent reactions are like those of fatty acid oxidation. Isoleucine yields acetyl CoA and propionyl CoA, whereas valine yields CO₂ and propionyl CoA. Propionyl CoA can be converted into the citric acid cycle intermediate succinyl CoA. The degradation of leucine, valine, and isoleucine confirm a point made earlier (Chapter 15): the number of reactions in metabolism is large, but the number of kinds of reactions is relatively small. The degradation of leucine, valine, and isoleucine provides a striking illustration of the underlying simplicity and elegance of metabolism.

The degradation of the aromatic amino acids is not as straightforward as that of the amino acids considered so far, although the final products—acetoacetate, fumarate, and pyruvate—are common intermediates. For the aromatic amino acids, molecular oxygen is used to break the aromatic ring.

The degradation of phenylalanine begins with its hydroxylation to tyrosine, a reversible reaction catalyzed by phenylalanine hydroxylase. This enzyme is called a monooxygenase or mixed-function oxygenase because one atom of the O₂ appears in the product and the other in H₂O:

The reductant here is tetrahydrobiopterin, a cofactor of phenylalanine hydroxylase derived from the cofactor biopterin. NADH is used to regenerate tetrahydrobiopterin from the quinonoid form that was produced in the hydroxylation reaction. The sum of the reactions is

Note that these reactions can also be used to synthesize tyrosine from phenylalanine.

The next step in the degradation of phenylalanine and tyrosine is the transamination of tyrosine to p-hydroxyphenylpyruvate (Figure 30.11). This α-ketoacid then reacts with O₂ to form homogentisate, to eventually yield fumarate and acetoacetate.

Tryptophan degradation requires several oxygenases to cleave its two rings to ultimately yield acetoacetate (Figure 30.12). Nearly all cleavages of aromatic rings in biological systems are catalyzed by dioxygenases. In contrast with monooxygenases, dioxygenases incorporate both oxygen atoms into the reaction product.

Methionine is converted into succinyl CoA in nine steps (Figure 30.13). The first step is the adenylation of methionine to form S-adenosylmethionine (SAM). Methyl donation and deadenylation yield homocysteine, which is metabolized to propionyl CoA, which, in turn, is processed to succinyl CoA, as was described above. Recall that S-adenosylmethionine plays a key role in cellular biochemistry as a common methyl donor in the cell (Chapter 29).