Starting point.

Pyrimidine
PRPP, and Nucleotides Are Made from
Carbamoyl
The common Phosphat e Aspart a te,
pyrimidine ribonucleotides
monophosphate (UMP; cytidylate) and uridine
(CMP; are cytidine 55-
monophosphat e
pyrimidines cytosine anduridylate),
uracil. De which contain the
cleotide biosynthesis
what different (Fig. 22-36) novo pyrimidine nu
sis; the manner from proceeds in a some
purine nucleotide synthe
six-membered
then attached to ribosepyrimidine ring is made first and
process is carbamoyl 5-phosphate. Required in this
the urea cycle (see phosphate, also an
Fig. intermediate in
I8-10). However, as we noted
FIGURE 22-36 De novo synthesis of
thesis of UTP and CTP via pyrimidine nucleotides: biosyn
orotidylate. The
from carbamoyl phosphate and pyrimidine is constructed
then added to the aspartate. The ribose 5-phosphate is
completed pyrimidine ring by orotate phosphori
bosyltransferase. The first step in this pathway (not
Fig. 18-1la) is the synthesis of shown here; see
NHÊ,catalyzed in eukaryotes tby carbamoyl phosphate from CO, and
carbamovt phosphate svnthetase .
 Aspartate
Carbamoyl
aspartate phosphate
trans
carbamoylase
P

H,N
NCarbamoylaspartate CH,
CH-C00
dihydroorotase
H0

L-Dihydroorotate HN
CH,
N
NAD H

dihydroorotate
dehydrogenase
NADH + Ht
HN ÇH
Orotate
CO0
H
PRPP
orotate
phosphoribosyl
transferase HN CH
’ PP;

Orotidylate P-oCH, CO0

H
H H
orotidylate ÓH OH
decarboxylase
HN CH
CH
Uridylate (UMP) P-0-CH,
H H
2 ATP

kinases OH OH

’ 2ADP

Uridine 5'-triphosphate (UTP)

Gin

cytidylate Glu
synthetase
ATP
NH,

CH
ADP + P, CH

P-P P-0-CH,
H

OH OH

Cytidine 5-triphosphate (CTP)

 Nucleotides, and Relate
Biosynthesis of Amino Acids,
Chapter 22
868

carbamoyl phosphate re
inanimals the mitochondria by car
in Chapter 18,synthesis is made in
quired in urea synthetase I,whereas the carbamoyl
bamovlphosphate pyrimidine biosynthesis is
made
phosphate required in enzyme, car
adifferent form of the
in the cytosol by synthetase II. In bacteria, a sin
bamoyl phosphate phosphate for the syn
gle enzyme supplies carbamoyl
bacterial enzyme
thesis of arginine and pyrimidines. The along a channel
has three separate active sites, spaced carbamoyl
nearly 100 A long (Fig. 22-37). Bacterial
illustration of the
phosphatesynthetase provides a vivid
channeling of unstable reaction intermediates between
active sites.
Carbamoyl phosphate reacts with aspartate to yield
N-carbamoylaspartate in the first committed step of
pyrimidine biosynthesis (Fig. 22-36). This reaction is
catalyzed by aspartate transcarbamoylase. In bacte
ria, this step is highly regulated, and bacterial aspartate
transcarbamoylase is one of the most thoroughly stud
ied allosteric enzymes (see below). By removal of wa
ter from N-carbamoylaspartate, a reaction catalyzed by
dihydroorotase, the pyrimidine ring is closed to form
L-dihydroorotate. This compound is oxidized to the
pyrimidine derivative orotate,a reaction in which NAD
is the ultimate electron acceptor. In
three enzymes in this eukaryotes, the first
synthetase I, pathway-carbamoyl phosphate
aspartate
droorotase-are transcarbamoylase,
part of a single trifunctional
and dihy
FIGURE
Theprotein, known by the acronym protein.
CAD,contains three phospha
identical polypeptide chains (each of M, alyzed b
with active sites for all three 230,000), cach small su
that large, multienzyme reactions. This suggests
this pathway. complexes may be the rule in between
A glutan
Once orotate is formed,the amido n
chain, provided once again by riboseis 5-phosphate side tion. Tho
orotidylate PRPP, attached to yield
(Fig. 22-36). Orotidylate site, whe
lated to uridylate, which is is then
decarboxy (bound A
is formed from phosphorylated
UTP by the action of to UTP. CTP the third
thetase, by way of an acyl cytidylate syn phate (h
phosphate intermediate
(consuming one ATP). The nitrogen
glutamine, although the cytidylate donor is normally
species can use NH; directly. synthetases in many not b
Imaxim