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Chapter 29
Chapter 29
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
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.
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