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 a striking example of the remarkable economy of metabolic conversions, as well as an illustration of 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. Amino acids that are degraded to pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate are termed glucogenic amino acids. The net synthesis of glucose from these amino acids is feasible because these citric acid cycle intermediates and pyruvate can be converted into phosphoenolpyruvate and then into glucose (Section 16.3.2). Recall that mammals lack a pathway for the net synthesis of glucose from acetyl CoA or acetoacetyl CoA.
Glucogenic amino acids are shaded red, and ketogenic amino acids are shaded yellow. Most amino acids are both glucogenic and ketogenic.
). 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. This classification is not universally accepted, because different quantitative criteria are applied. Whether an amino acid is regarded as being glucogenic, ketogenic, or both depends partly on the eye of the beholder. We will identify the degradation pathways by the entry point into metabolism.
Pyruvate is the point of entry for alanine, serine, cysteine, glycine, threonine, and tryptophan.
). The transamination of alanine directly yields pyruvate.
As mentioned previously (Section 23.3.1), 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 (Section 23.3.4).
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 enzymatic addition of a hydroxymethyl group or it can be cleaved to give CO2, NH4+, and an activated one-carbon unit (Section 24.2.6). Threonine can give rise to pyruvate through the intermediate aminoacetone. 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 (Section 23.4.2). Fumarate is also a point of entry for half the carbon atoms of tyrosine and phenylalanine, as will be discussed shortly.
α-Ketoglutarate is the point of entry of several five-carbon amino acids that are first converted into glutamate.
).
Conversion of histidine into glutamate.
). 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, a carrier of activated one-carbon units (Section 24.2.6).
Conversion of proline and arginine into glutamate.
).
Conversion of methionine, isoleucine, and valine into succinyl CoA.
). The mechanism for the interconversion of propionyl CoA and methylmalonyl CoA was presented in Section 22.3.3. 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 (Section 22.3.2).
The pathway for the conversion of methionine into succinyl CoA. S-Adenosylmethionine, formed along this pathway, is an important molecule for transferring methyl groups.
). The first step is the adenylation of methionine to form S-adenosylmethionine (SAM), a common methyl donor in the cell (Section 24.2.7). Methyl donation and deadenylation yield homocysteine, which is eventually processed to α-ketobutyrate. The enzyme α-ketoacid dehydrogenase complex oxidatively decarboxylates α-ketobutyrate to propionyl CoA, which is processed to succinyl CoA as described in Section 23.3.3.The degradation of the branched-chain amino acids employs reactions that we have encountered previously 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 branched-chain α-ketoacid dehydrogenase, a multienzyme complex, is a homolog of pyruvate dehydrogenase (Section 17.1.1) and α-ketoglutarate dehydrogenase (Section 17.1.6). 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 isovaleryl CoA 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-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 (Section 22.3.5).
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 14): 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 previously discussed, although the final products—acetoacetate, fumarate, and pyruvate—are common intermediates. For the aromatic amino acids, molecular oxygen is used to break an 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.
Tetrahydrobiopterin can be formed by the reduction of either of two forms of dihydrobiopterin.
). NADH reduces the quinonoid form of dihydrobiopterin produced in the hydroxylation of phenylalanine back to tetrahydrobiopterin in a reaction catalyzed by dihydropteridine reductase. 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 pathway for the conversion of phenylalanine into acetoacetate and fumarate.
). 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.
The pathway for the conversion of tryptophan into alanine and acetoacetate.
Mutations in the genes encoding this enzyme cause phenylketonuria. More than 200 point mutations have been identified in these genes. The positions of five mutations affecting the active site (blue), the biopterin-binding site (red), and other regions of the protein (purple) are indicated as colored spheres.
). 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-hydroxyanthranilic acid is cleaved with another dioxygenase and subsequently processed to acetoacetyl CoA (Figure 23.31). Nearly all cleavages of aromatic rings in biological systems are catalyzed by dioxygenases, a class of enzymes discovered by Osamu Hayaishi. The active sites of these enzymes contain iron that is not part of heme or an iron- sulfur cluster.
