section 27.11
Catabolism of Pyrimidine Nucleotides
643
C ytosine
NH,
HN
Uracil
O
T h y m in e
O
H20
NH
3
_____
«
2
*
C y to sin e
d e a m in a s e
HN
N '
H
H+ , NADPH
NADPt^
HN
D ih y d ro u racil
I
c r ^ N '
H
H ,o>
HN
•CH,
' N '
H
D ih y d ro p y rim id in e
d e h y d r o g e n a s e
HN
^ N A D P H , H
^ -N A D P +
.CH,
D ih y d ro th y m in e
O
N'
H
r
(5 -U re id o p ro p io n ate
(N -c a rb a m o y l- p -a la n in e )
OOC
NH,
^ Ç H
D ih y d ro p y rim id in a se
"O O C
H ,0
O
N
H P >
NH2
Ç H
C H 3
I
|
p -U re id o is o b u ty ra te
^
C H *
O
N
H
'H P
I -U re id o p ro p io n ase
n h * +
co 2 +
c o o
I
CH2
P -A lan in e C H 2
+ N H ,
COO
!
CHCH.
L
+ c o 2
+ n h ;
p -A m in o iso b u ty ra te
F IG U R E 2 7 -3 1
Pathways for pyrimidine catabolism. The major end product from cytosine and uracil is /3-alanine, from thymine it is
jS-aminoisobutyrate.
salvage pathways, PRPP is the substrate for HPRT
and APRT. In the pyrimidine pathway, PRPP activates
CPS II, may induce Pyr 1-3, and is a rate-limiting
substrate for orotate phosphoribosyltransferase. Thus,
changes in the levels of PRPP bring about concordant
changes, while enhanced utilization by one pathway
might result in reciprocal changes in the other. This
interrelationship between the synthesis of purine and
pyrimidine nucleotides was seen in a patient who had
a deficiency of PRPP synthetase and exhibited orotic
aciduria and hypouricemia, consistent with decreased
synthesis of purine and pyrimidine nucleotides.
2. Coordination of synthesis of purine and pyrimidine
nucleotides is affected by activation of CPS II by ATP.
3. Cultured mammalian cells (e.g., human lymphocytes)
fail to grow when exposed to adenosine and have
increased pools of ADP, ATP, and GTP, decreased
pools of UDP, UTP, and CTP, and decreased
incorporation of [
14
C] orotic acid. These effects are
reversed by exogenous uridine. These results suggest
that adenosine inhibits the conversion of orotic acid to
orotidine-5'-monophosphate. Adenosine deaminase
reduces the toxic effect of adenosine by converting it
to inosine. Increased levels of purine nucleotides may
also inhibit PRPP synthesis. This inhibition of
formation of pyrimidine nucleotides in the presence
of excess purine nucleosides and nucleotides has been
termed “pyrimidine starvation.”
27.11
Catabolism of Pyrimidine Nucleotides
Pyrimidine catabolism occurs mainly in the liver. In
contrast to purine catabolism, pyrimidine catabolism
yields
highly
soluble end products.
Pyrimidine
nu-
cleotides are converted to nucleosides by 5'-nucleotidase.
