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. We see here an example of the remarkable economy of metabolic conversions.

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. 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, can be converted into phosphoenolpyruvate and then into glucose (Section 16.3). Recall that mammals lack a pathway for the net synthesis of glucose from acetyl CoA or acetoacetyl CoA.

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Of the basic set of 20 amino acids, only leucine and lysine are solely ketogenic (Figure 23.20). 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 classed as solely glucogenic. We will identify the degradation pathways by the entry point into metabolism.

Pyruvate is the entry point of the three-carbon amino acids—alanine, serine, and cysteine—into the metabolic mainstream (Figure 23.21). The transamination of alanine directly yields pyruvate.

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As mentioned earlier in the chapter, glutamate is then oxidatively deaminated, yielding NH₄⁺ and regenerating α-ketoglutarate. The sum of these reactions is

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

Cysteine can be converted into pyruvate by several pathways, with its sulfur atom emerging in H₂S, SCN⁻, or SO₃²⁻.

The carbon atoms of three other amino acids 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 give CO₂, NH₄⁺, and an activated one-carbon unit. Threonine can give rise to pyruvate through the intermediate 2-amino-3-ketobutyrate. 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.

Recall that aspartate can also be converted into fumarate by the urea cycle (Figure 23.16). Fumarate is 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 is then oxidatively deaminated by glutamate dehydrogenase to yield α-ketoglutarate (Figure 23.22).

Histidine is converted into 4-imidazolone 5-propionate (Figure 23.23). 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 the transfer of its formimino group to tetrahydrofolate, a carrier of activated one-carbon units (Figure 24.9).

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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 23.24).

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 23.25). This pathway from propionyl CoA to succinyl CoA is also used in the oxidation of fatty acids that have an odd number of carbon atoms. The mechanism for the interconversion of propionyl CoA and methylmalonyl CoA was presented in Section 22.3.

Methionine is converted into succinyl CoA in nine steps (Figure 23.26). The first step is the adenylation of methionine to form S-adenosylmethionine (SAM), a common methyl donor in the cell (Section 24.2). Loss of the methyl and adenosyl groups yields homocysteine, which is eventually processed to α-ketobutyrate. This α-ketoacid is oxidatively decarboxylated by the α-ketoacid dehydrogenase complex to propionyl CoA, which is processed to succinyl CoA, as described in Section 22.3.

The branched-chain amino acids are degraded by 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.

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The α-ketoacids of valine and isoleucine, the other two branched-chain aliphatic amino acids, also are substrates (as is α-ketobutyrate derived from methionine). The oxidative decarboxylation of these α-ketoacids is analogous to that of pyruvate to acetyl CoA and of α-ketoglutarate to succinyl CoA. The branched-chain α-ketoacid dehydrogenase, a multienzyme complex, is a homolog of pyruvate dehydrogenase (Section 17.1) and α-ketoglutarate dehydrogenase (Section 17.2). Indeed, the E3 components of these enzymes, which regenerate the oxidized form of lipoamide, are identical.

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

β-Methylglutaconyl CoA is then hydrated to form 3-hydroxy-3-methyl-glutaryl 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 (Section 22.3).

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The degradative pathways of valine and isoleucine resemble that of leucine. After transamination and oxidative decarboxylation to yield a CoA 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. The degradation of leucine, valine, and isoleucine validate 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 yields the common intermediates acetoacetate, fumarate, and pyruvate. The degradation pathway is not as straightforward as that of the amino acids previously discussed. 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 reaction catalyzed by phenylalanine hydroxylase. This enzyme is called a monooxygenase (or mixed-function oxygenase) because one atom of O₂ appears in the product and the other in H₂O.

The reductant here is tetrahydrobiopterin, an electron carrier that has not been previously discussed and is derived from the cofactor biopterin. Because biopterin is synthesized in the body, it is not a vitamin. The quinonoid form of dihydrobiopterin is produced in the hydroxylation of phenylalanine. It is reduced back to tetrahydrobiopterin by NADPH in a reaction catalyzed by dihydropteridine reductase.

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The sum of the reactions catalyzed by phenylalanine hydroxylase and dihydropteridine reductase 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 23.27). This α-ketoacid then reacts with O₂ to form homogentisate. The enzyme catalyzing this complex reaction, p-hydroxyphenylpyruvate hydroxylase, is called a dioxygenase because both atoms of O₂ become incorporated into the product, one on the ring and one in the carboxyl group. The aromatic ring of homogentisate is then cleaved by O₂, which yields 4-maleylacetoacetate. This reaction is catalyzed by homogentisate oxidase, another dioxygenase. 4-Maleylacetoacetate is then isomerized to 4-fumarylacetoacetate by an enzyme that uses glutathione as a cofactor. Finally, 4-fumarylacetoacetate is hydrolyzed to fumarate and acetoacetate.

Tryptophan degradation requires several oxygenases (Figure 23.28). Tryptophan 2,3-dioxygenase cleaves the pyrrole ring, and kynureinine 3-monooxygenase hydroxylates the remaining benzene ring, a reaction similar to the hydroxylation of phenylalanine to form tyrosine. Alanine is removed and the 3-hydroxyanthranilate is cleaved by another dioxygenase and subsequently processed to acetoacetyl CoA. Nearly all cleavages of aromatic rings in biological systems are catalyzed by dioxygenases. The active sites of these enzymes contain iron that is not part of heme or an iron–sulfur cluster.

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