chapter 17
Protein and Amino Acid Metabolism
takes up significant quantities of valine and
may be a major (if not primary) site of utilization of
branched-chain amino acids. Glutamate, aspartate, and
glycine are
Glutamate is a precursor of
y-aminobutyrate; tyrosine of dopamine, norepinephrine,
and epinephrine; and tryptophan of serotonin, all of which
are neurotransmitters. Inactivation of neurotransmitters in-
volves deamination with production of ammonia, which is
removed by formation of glutamine. N-acetylaspartate oc-
curs in high levels in the brain but its function is not known.
It is synthesized from acetyl-CoA and aspartic acid cat-
alyzed by acetyl-CoA aspartate N-acetyl transferase. As-
partoacylase catalyzes the hydrolysis of N-acetylaspartate
to acetate and aspartic acid. The deficiency of aspartoa-
cylase, which is inherited as an autosomal recessive trait,
is associated with degenerative brain changes. Patients of
this disorder, also known as
Canavan dystrophy,
are usu-
ally of Eastern European Jewish heritage.
17.2 Metabolism of Ammonia
(at physiological pH, 98.5% exists as N H j), the
highly toxic product of protein catabolism, is rapidly in-
activated by a variety of reactions. Some products of these
reactions are utilized for other purposes (thus salvaging a
portion of the amino nitrogen), while others are excreted.
The excreted form varies quite widely among vertebrate
and invertebrate animals. The development of a pathway
for nitrogen disposal in a species appears to depend chiefly
on the availability of water. Thus, urea is excreted in
terrestrial vertebrates (
ureotelic organisms)',
ammonia in
aquatic animals (
ammonotelic organisms)',
and uric acid
(in semisolid form) in birds and land-dwelling reptiles
(uricotelic organisms).
During their aquatic phase of
development amphibia excrete ammonia but the adult frog
excretes urea; during metamorphosis the liver produces the
enzymes required for their synthesis. In humans, ammonia
is excreted mostly as urea, which is highly water-soluble,
is distributed throughout extracellular and intracellular
body water, is nontoxic and metabolically inert, has a high
nitrogen content (47%), and is excreted via the kidneys.
Ammonia is produced by deamination of glutamine,
glutamate, other amino acids, and adenylate. A consid-
erable quantity is derived from intestinal bacterial en-
zymes acting on urea and other nitrogenous compounds.
The urea comes from body fluids that diffuse into the in-
testine, and the other nitrogenous products are derived
from intestinal metabolism (e.g., glutamine) and ingested
protein. The ammonia diffuses across the intestinal mu-
cosa to the portal blood and is converted to urea in the
Ammonia is particularly toxic to brain but not to
other tissues, even though levels in those tissues may
increase under normal physiological conditions (e.g., in
muscle during heavy exercise in kidney during metabolic
acidosis). Several hypotheses have been suggested to
explain the mechanism of neurotoxicity.
In brain mitochondria, excess ammonia may drive the
reductive amination of a-ketoglutarate by glutamate de-
hydrogenase. This step may deplete a key intermedi-
ate of the TCA cycle and lead to its impairment, with
severe inhibition of respiration and considerable stim-
ulation of glycolysis. Since the [NAD+]/[NADH] ratio
will be high in mitochondria, there will be a decrease
in the rate of production of ATP. This hypothesis does
not explain why the same result does not occur in tis-
sues that are not affected by ammonia. A more plau-
sible hypothesis is depletion of glutamate which is an
excitatory neurotransmitter. Glutamine, synthesized and
stored in glial cells, is the most likely precursor of glu-
tamate. It is transported into the neurons and hydrolyzed
by glutaminase. Ammonia inhibits glutaminase and de-
pletes the glutamate concentration. A third hypothesis
invokes neuronal membrane dysfunction, since elevated
levels of ammonia produce increased permeability to K+
and Cl- ions, while glycolysis increases H+ ion concen-
tration (NHj stimulates
-phosphofructokinase; Chap-
ter 13). Encephalopathy of hyperammonemia is charac-
terized by brain edema and astrocyte swelling. Edema and
swelling have been attributed to intracellular accumulation
of glutamine which causes osmotic shifts of water into the
Behavioral disorders such as
sleep distur-
bances, and
pain insensitivity
associated with hyperam-
monemia have been attributed to increased tryptophan
transport across the blood-brain barrier and the accumu-
lation of its metabolites. Two of the tryptophan-derived
metabolites are serotonin and quinolinic acid (discussed
later). The latter is an excitotoxin at the N-methyl-D-
aspartate (NMDA) glutamate receptors. Thus, the mecha-
nism of the ammonium-induced neurological abnormali-
ties is multifactorial. Normally only small amounts of NH
(i.e., NH^ ) are present in plasma, since NH
is rapidly re-
moved by reactions in tissues of glutamate dehydrogenase,
glutamine synthase, and urea formation.
Urea Synthesis
contained in the blood flowing through the hep-
atic lobule is removed by the hepatocytes and converted
into urea. Periportal hepatocytes are the predominant sites
of urea formation. Any ammonia that is not converted
to urea may be incorporated into glutamine catalyzed
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