344
chapter 17
Protein and Amino Acid Metabolism
O P R T
v p p
P R PP
Allopurinol -
XO
►Oxipurinol
PR T
PR PP
7 "y
r>
T
Oxipurinol
Ribonucleotide
Orotidine 5 -Monophosphate (O M P )------- -»-Orotidine
O M P
Decarboxylase
PP
Uridine 5 -Monophosphate
FIGURE 17-8
The metabolic interrelationship between mitochondrial carbamoyl phosphate synthesis to urea formation and to
cytosolic carbamoyl phosphate channeled into pyrimidine biosynthesis. In
o r n ith in e tra n sc a rb a m o y la se (O T C )
d eficien cy,
mitochondrial carbamoyl phosphate diffuses into the cytosol and stimulates pyrimidine biosynthesis, leading
to
o ro tid in u ria .
Administration of allopurinol augments orotidinuria by increasing the flux in the pyrimidine
biosynthetic pathway. CPS = Carbamoyl phosphate synthase, AT = aspartate transcarbamoylase, D = dihydroorotase,
DH = dihydroorotate dehydrogenase, OPRT = orotate phosphoribosyltransferase, XO = xanthine oxidase,
PRT = phosphoribosyltransferase, PRPP = 5-phosphoribosyl-1-pyrophosphate.
of nitrogen to products other than urea is achieved by ad-
ministration of sodium benzoate or sodium (or calcium)
phenylacetate. Administration of benzoate leads to elimi-
nation of hippurate (benzoylglycine):
phosphate, catalyzed by mitochondrial glycine synthase
(glycine cleavage enzyme).
Phenylacetate or phenylbutyrate administration in-
creases excretion of phenylacetylglutamine:
o
— O ~ + A T P
4
" + CoASH
Activating enzyme
Benzoate
< n
O
-C — S — C oA + A M P 2" + P P T -
B enzoyl-C oA
< ^ - C H
3- C O O " + A TP4" + COASH A C W n g ” Zy^
< 0 K C H 3- C - S C O A + A M P -+ PP,=
Phenylacetyl-CoA
CONH?
CONH2
I
I
O
<CH2)2
^
‘f n * Conjugating enzyme <
+ CoASH + H*
fi
y -C H j— C— SCoA + Hj^N— CH
COO"
Glutamine
Phenylacetylglutamine
H
COO"
Hippurate is rapidly secreted since its clearance is five
times greater than its glomerular filtration rate. The glycine
nitrogen is derived from ammonia in a complex reaction
that uses CO
2
, NADH, N5,N10-methylenetetrahydrofolate
(a source of a single carbon unit; Chapter 27) and pyridoxal
The excretion of phenylacetylglutamine produces loss of
two nitrogen atoms.
NAG synthase deficiency cannot be treated by admin-
istration of NAG, since NAG undergoes cytosolic inacti-
vation by deacylation and is not readily permeable across
the inner mitochondrial membrane. An analogue of NAG,
