Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates

II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic
Intermediates
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.
Of the basic set of 20 amino acids, only leucine and lysine are solely ketogenic (Figure 23.21). 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.
23.5.1. Pyruvate as an Entry Point into Metabolism
Pyruvate is the entry point of the three-carbon amino acids alanine, serine, and cysteine
mainstream (Figure 23.22). The transamination of alanine directly yields pyruvate.
into the metabolic
As mentioned previously (Section 23.3.1), glutamate is then oxidatively deaminated, yielding NH4 + and regenerating αketoglutarate. 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 SO3 2-.
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.
23.5.2. Oxaloacetate as an Entry Point into Metabolism
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.
23.5.3. Alpha-Ketoglutarate as an Entry Point into Metabolism
The carbon skeletons of several five-carbon amino acids enter the citric acid cycle at α -ketoglutarate. These amino
acids are first converted into gluta-mate, which is then oxidatively deaminated by glutamate dehydrogenase to yield αketoglutarate (Figure 23.23).
Histidine is converted into 4-imidazolone 5-propionate (Figure 23.24). 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).
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 23.25).
23.5.4. Succinyl Coenzyme A Is a Point of Entry for Several Nonpolar Amino Acids
Succinyl CoA is a point of entry for some of the carbon atoms of methio-nine, isoleucine, and valine. Propionyl CoA and
then methylmalonyl CoA are intermediates in the breakdown of these three nonpolar amino acids (Figure 23.26). 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).
23.5.5. Methionine Degradation Requires the Formation of a Key Methyl Donor, SAdenosylmethionine
Methionine is converted into succinyl CoA in nine steps (Figure 23.2.7). 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.
23.5.6. The Branched-Chain Amino Acids Yield Acetyl CoA, Acetoacetate, or
Propionyl CoA
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 αketoacid 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 βmethylcrotonyl 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.
23.5.7. Oxygenases Are Required for the Degradation of Aromatic Amino Acids
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 O appears in
2
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. Tetrahydrobiopterin is initially
formed by the reduction of dihydrobiopterin by NADPH in a reaction catalyzed by dihydrofolate reductase (Figure
23.28). 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 next step in the degradation of phenylalanine and tyrosine is the transamination of tyrosine to phydroxyphenylpyruvate (Figure 23.29). 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 O
become incorporated into the product, one on the ring and one in the carboxyl group. The aromatic ring of
2
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 23.30). 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.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.21. Fates of the Carbon Skeletons of Amino Acids. Glucogenic amino acids are shaded red, and ketogenic
amino acids are shaded yellow. Most amino acids are both glucogenic and ketogenic.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.22. Pyruvate Formation from Amino Acids. Pyruvate is the point of entry for alanine, serine, cysteine,
glycine, threonine, and tryptophan.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.23. α -Ketoglutarate formation from amino acids. α-Ketoglutarate is the point of entry of several fivecarbon amino acids that are first converted into glutamate.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.24. Histidine Degradation. Conversion of histidine into glutamate.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.25. Glutamate Formation. Conversion of proline and arginine into glutamate.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.26. Succinyl CoA Formation. Conversion of methionine, isoleucine, and valine into succinyl CoA.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.27. Methionine Metabolism. The pathway for the conversion of methionine into succinyl CoA. SAdenosylmethionine, formed along this pathway, is an important molecule for transferring methyl groups.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.28. Formation of Tetrahydrobiopterin, an Important Electron Carrier. Tetrahydrobiopterin can be
formed by the reduction of either of two forms of dihydrobiopterin.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates
Figure 23.29. Phenylalanine and Tyrosine Degradation. The pathway for the conversion of phenylalanine into
acetoacetate and fumarate.
II. Transducing and Storing Energy
23. Protein Turnover and Amino Acid Catabolism
23.5. Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates