section 17.2
Metabolism of Ammonia
343
the enzymes discussed above, an exogenous supply of
arginine is required.
Formation o f Urea and Ornithine
This irreversible reaction is catalyzed by arginase in the
cytosol:
n h
2
1
c =
n h 2 +
1
N H 3+
1
1
NH
C H
2
1
n h
2
1
C H
2
1
C H
2
1
+
H
2 0
—
►
c = o
+
1
1
C H
2
C H
2
1
N H j
1
C H
2
1
C H N H 3 +
j
1
C H N H 3 +
C O O "
C O C T
L-A rginine
U rea
L -O rnithine
The urea so formed is distributed throughout the body wa-
ter and excreted. The renal clearance of urea is less than
the glomerular filtration rate because of passive tubular
back-diffusion. Diffusion of urea in the intestine leads to
formation of ammonia, which enters the portal blood and
is converted to urea in liver. Reentry of ornithine into mi-
tochondria initiates the next revolution of the urea cycle.
Ornithine can be converted to glutamate-y-semialdehyde
(which is in equilibrium with its cyclic form A'-pyrrolinc-
5-carboxylate) by ornithine aminotransferase and de-
carboxylated to putrescine by ornithine decarboxylase.
Ornithine is also produced in the arginine-glycine trans-
amidinase reaction.
The availability of substrates (ammonia and amino
acids) in the liver determines the amount of urea syn-
thesized. Urea excretion increases with increased protein
intake and decreases with decreased protein intake.
Energetics o f Ureagenesis
The overall reaction of ureagenesis is
NH
3
+ HCO^ + aspartate + 3ATP —►
urea + fumarate + 2ADP + 4P; + AMP
Hydrolysis of four high-energy phosphate groups is
required for the formation of one molecule of urea. If
fumarate is converted to aspartate (by way of malate and
oxaloacetate), one NADH molecule is generated that can
give rise to three ATP molecules through the electron
transport chain, so that the energy expenditure becomes
one ATP molecule per each molecule of urea.
Hyperammonemias
Hyperammonemias
are caused by inborn errors of ure-
agenesis and organic acidemias, liver immaturity (tran-
sient hyperammonemia of the newborn), and liver failure
(hepatic encephalopathy). Neonatal hyperammonemias
are characterized by vomiting, lethargy, lack of appetite,
seizures, and coma. The underlying defects can be iden-
tified by appropriate laboratory measurements (e.g., as-
sessment of metabolic acidosis if present and character-
ization of organic acids, urea cycle intermediates, and
glycine).
Inborn errors of the six enzymes of ureagenesis and
NAG synthase have been described. The inheritance pat-
tern of the last is not known, but five of the urea cycle
defects are autosomal recessive and ornithine carbamoyl-
transferase (OCT) deficiency is X-linked.
Carriers of OCT deficiency (estimated to be several
thousand women in the U.S. A.) can be identified by admin-
istration of a single oral dose of allopurinol, a purine ana-
logue, followed by measurement of urinary orotidine ex-
cretion. The underlying principle of this assay is that when
the intramitochondrial carbamoyl phosphate accumulates
in OCT heterozygotes, it diffuses into the cytoplasm stimu-
lating the biosynthesis of pyrimidines. One of the interme-
diates in this pathway—
orotidine
—accumulates, leading
to
orotidinuria
(Figure 17-8).
The sensitivity of this test is increased by increas-
ing the flux in the pyrimidine biosynthetic pathway. The
enhanced flux is accomplished by allopurinol, which by
way of oxypurinol ribonucleotide inhibits the forma-
tion of final product uridine 5'-phosphate (UMP) in the
pyrimidine biosynthesis (Chapter 27).
Antenatal diagnosis for fetuses at risk for the urea
cycle enzyme disorders can be made by appropri-
ate enzyme assays and DNA analysis in the cultured
amniocytes.
Acute
neonatal
hyperammonemia,
irrespective
of
cause, is a medical emergency and requires immediate
and rapid lowering of ammonia levels to prevent serious
effects on the brain. Useful measures include hemodialy-
sis, exchange transfusion, peritoneal dialysis, and admin-
istration of arginine hydrochloride. The general goals of
management are to
1. Decrease nitrogen intake so as to minimize the
requirement for nitrogen disposal,
2. Supplement arginine intake, and
3. Promote nitrogen excretion in forms other than urea.
The first can be accomplished by restriction of dietary
protein and administration of a-keto analogues of essen-
tial amino acids. Arginine supplementation as a precursor
of ornithine is essential to the urea cycle. The diversion
