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CHAPTER 29: CATABOLISM OF THE CARBON

SKELETONS OF AMINO ACIDS

BIOMEDICAL IMPORTANCE
Most disorders of amino acid catabolism are rare, but if left
untreated they can result in irreversible brain damage and
early mortality.
Prenatal or early postnatal detection of metabolic disorders
and timely initiation of treatment thus are essential.
The ability to detect the activities of enzymes in
cultured amniotic fluid cells facilitates prenatal diagnosis
by amniocentesis.
All states now conduct screening tests of newborns for
as up to 40 metabolic diseases.
These tests include, but are not limited to, disorders
associated with defects in the catabolism of amino acids.
The most reliable screening tests use tandem mass
spectrometry to detect, in a few drops of neonate blood,
catabolites suggestive of a given metabolic defect.
The metabolites detected pinpoint the metabolic defect
as the lowered or absent activity of a given enzyme.
Treatment consists primarily of feeding diets low in the amino
acid whose catabolism is impaired.
Mutations either of a gene or of associated regulatory regions
of DNA can result either in the:
failure to synthesize the encoded enzyme or
in synthesis of a partially or completely nonfunctional
enzyme
While some mutations do not adversely affect enzyme
activity, mutations that compromise an enzymes three-
TRANSAMINATION TYPICALLY INITIATES AMINO ACID
dimensional structure, or that disrupt catalytic or regulatory
CATABOLISM
sites of an enzyme, can have severe metabolic consequences.
Removal of -amino nitrogen by transamination, catalyzed by
Low catalytic efficiency of a mutant enzyme can result
an aminotransferase is the:
from impaired positioning of residues involved in
first catabolic reaction of most of the protein amino
catalysis, or in binding a substrate, coenzyme, or metal
acids
ion.
The exceptions are:
Mutations may also impair the ability of certain enzymes to
Proline
respond appropriately to the signals that modulate their
Hydroxyproline
activity by altering an enzymes affinity for an allosteric
Threonine
regulator of activity.
Lysine
Since different mutations can have similar effects on any
whose -amino groups do not participate in
of the above factors, various mutations may give rise to
transamination.
the same clinical signs and symptoms.
The hydrocarbon skeletons that remain are then degraded to
amphibolic intermediates as outlined in Figure 291.
AMINO ACIDS ARE CATABOLIZED TO INTERMEDIATES FOR
CARBOHYDRATE AND LIPID BIOSYNTHESIS
Asparagine & Aspartate Form Oxaloacetate
Nutritional studies in the period 1920 to 1940, reinforced and
All four carbons of asparagine and of aspartate form
confirmed by studies using isotopically labeled amino acids
oxaloacetate via reactions catalyzed by asparaginase and a
conducted from 1940 to 1950, established the
transaminase.
interconvertibility of the carbon atoms of fat, carbohydrate,
Metabolic defects in transaminases, which fulfill central
and protein.
amphibolic functions, may be incompatible with life.
These studies also revealed that all or a portion of the carbon
Consequently, no known metabolic defect is associated with
skeleton of every amino acid is convertible either to
this short catabolic pathway.
carbohydrate (13 amino acids), fat (one amino acid), or both
fat and carbohydrate (five amino acids) (Table 291). Figure
291 outlines overall aspects of these interconversions. Glutamine & Glutamate Form -Ketoglutarate

The catabolism of glutamine and of glutamate parallels that of

asparagine and aspartate in reactions catalyzed by

glutaminase and a transaminase that forms

ketoglutarate
While both glutamate and aspartate are substrates for the
same transaminase:
deamidation of their corresponding amides is catalyzed
by different enzymes, asparaginase, and glutaminase.
Possibly for the reason stated earlier, there are no known
metabolic defects of the glutamine-glutamate catabolic
pathway.

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Significant metabolic disorders are, however, associated with Arginase Arginemia
the catabolism of many other amino acids. Cystathionine--synthase Homocystinuria
These metabolic disorders are discussed below under the Fumarylacetoacetate hydrolase Type-I tyrosinemia (Tyrosinosis)
catabolism of each amino acid, and are summarized in Table 292. Glycine N-methyl-transferase Hypermethioninemia
Histidine ammonia lyase (Histidase) Histidinemia & urocanic acidemia
This table lists the impaired enzyme, its IUB enzyme catalog
Homogentisate oxidase Alkaptonuria. Homogentisate
(EC) number, a cross-reference to a specific figure and
excreted.
numbered reaction in this text, and a numerical link to the p-Hydroxyphenylpyruvate Neonatal tyrosinemia
Online Mendelian Inheritance in Man database (OMIM). hydroxylase
Proline Isovaleryl-CoA dehydrogenase Isovaleric acidemia
The catabolism of proline takes place in mitochondria. Branched chain a-ketoacid Branched-chain ketonuria (MSUD)
Since proline does not participate in transamination, its - decarboxylase complex
amino nitrogen is retained throughout a two-stage oxidation Methionine adenosyltransferase Hypermethioninemia
to glutamate. Ornithine--aminotransferase Ornithemia, gyrate atrophy
Phenylalanine hydroxylase Type I (classic) phenylketonuria
Oxidation to 1-pyrroline-5-carboxylate is catalyzed by:
Proline dehydrogenase Type I hyperprolinemia
proline dehydrogenase
1-Pyrroline-5-carboxylate Type II hyperprolinemia & hyper 4-
Subsequent oxidation to glutamate is catalyzed by:
dehydrogenase hydroxyprolinemia
1-pyrroline-5-carboxylate dehydrogenase (also called Saccharopine dehydrogenase Saccharopinuria
glutamate--semialdehde dehydrogenase) Tyrosine aminotransferase Type II tyrosinemia
TWO METABOLIC DISORDERS OF PROLINE CATABOLISM:
Inherited as autosomal recessive traits, both are CATABOLISM OF GLYCINE, SERINE, ALANINE, CYSTEINE,
consistent with a normal adult life. THREONINE, & 4-HYDROXYPROLINE
TYPE I HYPERPROLINEMIA
The metabolic block is at proline dehydrogenase. Glycine
There is no associated impairment of hydroxyproline The glycine cleavage complex of liver mitochondria splits
catabolism. glycine to CO2 and NH4+ and forms:
TYPE II HYPERPROLINEMIA N5, N10-methylene tetrahydrofolate
The metabolic block is at 1-pyrroline-5-carboxylate
dehydrogenase, which also participates in the Glycine + H4folate + NAD+ CO2 + NH3
catabolism of arginine, ornithine, and + 5,10-CH2-H4folate + NADH + H+
hydroxyproline.
Since proline and hydroxyproline catabolism are affected, The glycine cleavage systemconsists of:
both 1-pyrroline-5-carboxylate and 1-pyrroline- 3-hydroxy- Three enzymes and an H-protein that has a covalently
5-carboxylate are excreted. attached dihydrolipoyl moiety.
NONKETOTIC HYPERGLYCINEMIA:
Arginine & Ornithine a rare inborn error of glycine degradation presently
The initial reactions in arginine catabolism are conversion to known only in Finland
ornithine followed by transamination of ornithine to glycine accumulates in all body tissues including the
glutamate--semialdehyde. central nervous system
Subsequent catabolism of glutamate--semialdehyde to - PRIMARY HYPEROXALURIA:
ketoglutarate occurs as described for proline. failure to catabolize glyoxylate formed by the
Mutations in ornithine c-aminotransferase (ornithine deamination of glycine.
transaminase): Subsequent oxidation of glyoxylate to oxalate
elevate plasma and urinary ornithine and are associated results in:
with gyrate atrophy of the choroid and retina Urolithiasis
Treatment involves: Nephrocalcinosis
restricting dietary arginine Early mortality from renal failure or
HYPERORNITHINEMIA HYPERAMMONEMIA SYNDROME: hypertension
a defective mitochondrial ornithine-citrulline antiporter Glycinuria results from a defect in renal
impairs transport of ornithine into mitochondria where it tubular reabsorption
participates as an intermediate in urea synthesis Serine
Following conversion to glycine, catalyzed by:
Histidine glycine hydroxymethyltransferase
Catabolism of histidine proceeds via: serine catabolism merges with that of glycine
urocanate, 4-imidazolone- 5-propionate, and N-
formiminoglutamate (Figlu). Alanine
Formimino group transfer to tetrahydrofolate forms Transamination of -alanine forms pyruvate.
glutamate, then -ketoglutarate. Probably on account of its central role in metabolism there is
FOLIC ACID DEFICIENCY: no known metabolic defect of -alanine catabolism.
Transfer of the formimino group is impaired, and Figlu is
excreted. Cystine & Cysteine
Excretion of Figlu following a dose of histidine thus can Cystine is first reduced to cysteine by:
be used to detect folic acid deficiency. cystine reductase
Benign disorders of histidine catabolism include: Two different pathways then convert cysteine to
Histidinemia pyruvate
Urocanic aciduria associated with impaired histidase cysteine sulfinate pathway
3-mercaptopyruvate pathway
TABLE 29-2 Metabolic Diseases of Amino Acid Metabolism There are numerous abnormalities of cysteine metabolism.
DEFECTIVE ENZYME MAJOR SIGNS AND SYMPTOMS
Cystine, lysine, arginine, and ornithine are excreted in cystine-
S-Adenosylhomocysteine hydrolase Hypermethioninemia
lysinuria (cystinuria):
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a defect in renal reabsorption of these amino acids due to oxidation of homogentisate to benzoquinone
Apart from cystine calculi, cystinuria is benign. acetate, which polymerizes and binds to connective
The mixed disulfide of l-cysteine and l-homocysteine tissue.
excreted by: First described in the sixteenth century based on the
CYSTINOSIS (CYSTINE STORAGE DISEASE): observation that the urine darkened on exposure to air,
with deposition of cysteine crystals in tissues and alkaptonuria provided the basis for Sir Archibald
early mortality from acute renal failure Garrods early twentieth century classic ideas concerning
Epidemiologic and other data link plasma homocysteine levels heritable metabolic disorders.
to cardiovascular risk, but the role of homocysteine as a Based on the presence of ochronosis and on chemical
causal cardiovascular risk factor remains controversial. evidence, the earliest known case of alkaptonuria is,
however, its 1977 detection in an Egyptian mummy dating
Threonine from 1500 b.c.
Threonine aldolase cleaves threonine to:
glycine and acetaldehyde Phenylalanine
Oxidation of acetaldehyde to acetate is followed by formation Phenylalanine is first converted to tyrosine.
of acetyl-CoA. Subsequent reactions are those of tyrosine.
HYPERPHENYLALANINEMIAS:
arise from defects in phenylalanine hydroxylase (type I,
classic phenylketonuria (PKU), frequency 1 in 10,000
births), in dihydrobiopterin reductase (types II and III),
4-Hydroxyproline or in dihydrobiopterin biosynthesis (types IV and V)
Catabolism of 4-hydroxy-l-proline forms: Alternative catabolites are excreted.
l-1-pyrroline-3-hydroxy-5-carboxylate A diet low in phenylalanine can prevent the mental
-hydroxy-l-glutamate--semialdehyde retardation of PKU.
erythro--hydroxy-l-glutamate DNA probes facilitate prenatal diagnosis of defects in
-keto- -hydroxyglutarate phenylalanine hydroxylase or dihydrobiopterin reductase.
An aldol-type cleavage then forms glyoxylate plus pyruvate. Elevated blood phenylalanine may not be detectable until:
HYPERHYDROXYPROLINEMIA: 3 to 4 days postpartum
A defect in 4-hydroxyproline dehydrogenase which is False-positives in premature infants may reflect delayed
benign. maturation of enzymes of phenylalanine catabolism.
There is no associated impairment of proline catabolism. An older and less reliable screening test employs FeCl3:
A defect in glutamate-f-semialdehyde dehydrogenase: to detect urinary phenylpyruvate
is accompanied by excretion of 1-pyrroline- 3-hydroxy- FeCl3 screening for PKU of the urine of newborn
5-carboxylate infants is compulsory in many countries, but in the
United States has been largely supplanted by
ADDITIONAL AMINO ACIDS THAT FORM ACETYL-CoA tandem mass spectrometry.
Lysine
Tyrosine The first six reactions of l-lysine catabolism in human liver
Following transamination of tyrosine to p- form crotonyl-CoA, which is then degraded to acetyl-CoA by
hydroxyphenylpyruvate, successive reactions form: the reactions of fatty acid catabolism.
Maleylacetoacetate In what follows, circled numerals refer to the corresponding
Fumarylacetoacetate numbered reactions of Figure 2915.
Fumarate Reactions 1 and 2 convert the Schiff base formed between -
Acetoacetate ketoglutarate and the -amino group of lysine to l--
Acetyl-CoA aminoadipate-d-semialdehde.
Acetate Reactions 1 and 2 both are catalyzed by a single bifunctional
Several metabolic disorders are associated with the tyrosine enzyme, aminoadipate semialdehde synthase (EC 1.5.1.8) whose
catabolic pathway. N-terminal and C-terminal domains contain lysine--
TYPE I TYROSINEMIA(TYROSINOSIS): ketoglutarate reductase and saccharopine dehydrogenase
The probable metabolic defect is at fumarylacetoacetate activity, respectively.
hydrolase. Reduction of l--aminoadipate-d-semialdehde to l--
Therapy employs a diet low in tyrosine and phenylalanine. aminoadipate (reaction 3) is followed by transamination to -
Untreated acute and chronic tyrosinosis leads to death ketoadipate (reaction 4). Conversion to the thioester glutaryl-
from liver failure. CoA (reaction 5) is followed by the decarboxylation of
Alternate glutaryl- CoA to crotonyl-CoA (reaction 6).
TYPE II TYROSINEMIA (RICHNER-HANHART Subsequent reactions are those of fatty acid catabolism.
SYNDROME):
a defect in tyrosine aminotransferase
NEONATAL TYROSINEMIA:
due to lowered activity of p-hydroxyphenylpyruvate
hydroxylase
Therapy employs a diet low in protein.
ALKAPTONURIA:
The metabolic defect in is a defective homogentisate
oxidase
The urine darkens on exposure to air:
due to oxidation of excreted homogentisate
Late in the disease, there is arthritis and connective
tissue pigmentation (ochronosis):
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THE INITIAL REACTIONS ARE COMMON TO ALL THREE
BRANCHED-CHAIN AMINO ACIDS
The first three reactions of the catabolism of isoleucine,
leucine, and valine are analogous to reactions of fatty acid
catabolism.
Following transamination the carbon skeletons of the resulting
-keto acids undergo:
oxidative decarboxylation and
conversion to coenzyme A thioesters
This multistep process is catalyzed by the:
mitochondrial branched-chain -keto acid dehydrogenase
complex, whose components are functionally identical to
those of the pyruvate dehydrogenase complex (PDH).
Like PDH, the branchedchain -ketoacid dehydrogenase
complex consists of five components:
E1: thiamin pyrophosphate (TPP)-dependent
HYPERLYSINEMIA:
branchedchain
can result from a metabolic defect in either the first or
-ketoacid decarboxylase
second activity of the bifunctional enzyme aminoadipate
E2: dihydrolipoyl transacylase (contains lipoamide)
semialdehde synthase, but this is accompanied by
E3: dihydrolipoamide dehydrogenase (contains FAD)
elevated levels of blood saccharopine only if the defect
Protein kinase
involves the second activity.
Protein phosphatase
A metabolic defect at reaction 6 results in an inherited
As for pyruvate dehydrogenase:
metabolic disease that is associated with:
the protein kinase and protein phosphatase regulate
striatal and cortical degeneration
activity of the branched-chain -keto acid
is characterized by elevated concentrations of
dehydrogenase complex via phosphorylation (inactivation)
glutarate and its metabolites glutaconate and 3-
and dephosphorylation (activation)
hydroxyglutarate.
Dehydrogenation of the resulting coenzyme A thioesters
The challenge in management of these metabolic defects
proceeds like the dehydrogenation of lipid-derived fatty acyl-
is to restrict dietary intake of l-lysine without producing
CoA thioesters.
malnutrition.

Tryptophan
METABOLIC DISORDERS OF BRANCHED-CHAIN AMINO ACID
Tryptophan is degraded to amphibolic intermediates via:
CATABOLISM
the kynurenine-anthranilate pathway
MAPLE SYRUP URINE DISEASE:
Tryptophan 2,3-dioxygenase (tryptophan pyrrolase):
branched-chain ketonuria or MSUD
Opens the indole ring, incorporates molecular oxygen, and
ODOR OF URINE: maple syrup, or burnt sugar
forms N-formylkynurenine.
The biochemical defect in MSUD involves the:
Tryptophan oxygenase:
-keto acid decarboxylase complex
an iron porphyrin metalloprotein that is inducible in liver
Plasma and urinary levels of leucine, isoleucine, valine, and
by:
their -keto acids and -hydroxy acids (reduced -keto acids)
adrenal corticosteroids
are elevated, but the urinary keto acids derive principally
tryptophan
from leucine.
is feedback inhibited by nicotinic acid derivatives,
Signs and symptoms of MSUD include:
including NADPH
fatal ketoacidosis
Hydrolytic removal of the formyl group of N-
neurological derangements
formylkynurenine, catalyzed by kynurenine formylase,
mental retardation
produces kynurenine.
maple syrup odor of urine
Since kynureninase requires pyridoxal phosphate:
The mechanism of toxicity is unknown.
excretion of xanthurenate in response to a
Early diagnosis by enzymatic analysis is essential to avoid
tryptophan load is diagnostic of vitamin B6
brain damage and early mortality by replacing dietary protein
deficiency.
b an amino acid mixture that lacks leucine, isoleucine, and
HARTNUP DISEASE:
valine.
Reflects impaired intestinal and renal transport of
The molecular genetics of MSUD are heterogeneous.
tryptophan and other neutral amino acids.
MSUD can result from mutations in the genes that encode
Indole derivatives of unabsorbed tryptophan formed by
E1, E1, E2, and E3. Based on the locus affected, genetic
intestinal bacteria are excreted.
subtypes of MSUD are recognized.
The defect limits tryptophan availability for niacin
biosynthesis and accounts for the pellagra-like signs and
symptoms.

Methionine
Methionine reacts with ATP forming:
S-adenosylmethionine, active methionine
Subsequent reactions form propionyl-CoA which three
subsequent reactions convert to succinyl-CoA

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The impaired enzyme in is:
isovaleryl-CoA dehydrogenase
Vomiting, acidosis, and coma follow ingestion of excess
protein.
Accumulated isovaleryl-CoA is hydrolyzed to isovalerate and
excreted.

INTERMITTENT BRANCHED-CHAIN KETONURIA:

the -keto acid decarboxylase retains some activity, and
symptoms occur later in life In
ISOVALERIC ACIDEMIA:
ingestion of protein-rich foods elevates isovalerate, the
deacylation product of isovaleryl-CoA.

BIOCHEMISTRY|CATABOLISM OF PROTEINS AND AMINO ACID NITROGEN