section 17.2
Metabolism of Ammonia
341
F IG U R E 17-7
Formation of urea in hepatocytes. NAGS = N-acetylglutamate synthase; CPSI = carbamoylphosphate synthase I;
OCT = ornithine carbamoyltransferase; C-OT = citrulline-omithine translocase; AS = argininosuccinate synthase;
AL = argininosuccinate lyase; A = arginase. —©—
s- indicates the absolute requirement of N-acetylglutamate for
CPSI activity.
by glutamine synthase located in pericentral hepatocytes.
Formation of urea requires the combined action of two
enzymes to produce carbamoyl phosphate and of four
enzymes that function in a cyclic manner in the urea
cycle (Figure 17-7). Although some of these enzymes
occur in extrahepatic tissues and urea formation has been
shown to occur in several cell lines in tissue culture,
the most important physiological site of urea formation
is the liver. In hepatocytes the first three enzymes are
mitochondrial and the others are cytosolic. A citrulline-
omithine antiport is located in the inner mitochondrial
membrane.
of CoA derivatives that are also competitive inhibitors
of N-acetylglutamate synthase and inhibitors of CPSI.
Hyperammonemia
often accompanies organic acidemias.
c o c r
I
Arg
C O O '
0
(C H
2 ) 2
Il
I
C H
3
C — S C o A + C H N H 3+
I
C O O '
i
(C H
2 ) 2
I®
I
■J— C oA SH + C H N H C O C H
3
+ H +
I
^
C O O '
'
e
A cetyl-C oA
G lu ta m a te
" —
N -A cetyl-
g lu ta m a te
Formation o f Carbamoyl Phosphate
Carbamoyl phosphate synthesis requires amino acid
acetyltransferase (N-acetylglutamate synthase, mitochon-
drial) and carbamoyl-phosphate synthase I (CPSI). N-
Acetylglutamate (NAG) is an obligatory positive effector
of CPSI. NAG synthase is under positive allosteric mod-
ulation by arginine and product inhibition by NAG. De-
pletion of CoA-SH decreases NAG synthesis and ureage-
nesis. This situation can occur in
organic acidemias
(e.g.,
propionic acidemia; Chapter 18), in which organic acids
produced in excess compete for CoA-SH for formation
CPSI catalyzes the reaction
N H 4+ + H C 0 3 ' + 2A T P 4 '
NAG-K<|M9?* >
O
II
H
2
N — C — 0 P 0 32 ' + 2 A D P 3 ' + P 2 ' + 2 H +
NAG binding changes the conformation and subunit
structure of CPSI, with preponderance of the monomers.
Carbamoylglutamate is also an activator of CPSI. Glu-
tamate and «-ketoglutarate compete with NAG for bind-
ing. CPSI is subject to product inhibition by Mg-ADP. It
