642
chapter 27
Nucleotide Metabolism
(a) In h ib ito rs o f d e n o v o p y rim id in e b io s y n th e s is (by inhibiting o ro tid y late d e c a rb o x y la s e )
O
A z au rid in e R = — O H
O
II
A zarib in e
R = — O — C — C H 3
(b) In h ib ito rs o f n u c le ic a c id s y n th e s is ; a ls o in c o rp o ra te d into n u c le ic a c id s
C y ta ra b in e
(c y to s in e a ra b in o s id e ;
1
-p - o - a r a b in o f u r a n o
s y lcy to sin e )
H O C H ,
N = N = N
C H ,
3 '-A zid o -
3 '- d e o x y -
th y m id in e
(AZT)
(c) In h ib ito rs o f th y m id y la te s y n th a s e
H
F lu c y to s in e
(5 -flu o ro c y to s in e ;
c o n v e r ts to 5 -F U )
F IG U R E 2 7 -3 0
Pyrimidine analogues. All of these compounds require conversion to appropriate nucleotides before they become active.
biosynthesis, in particular by CTP (Chapter 7). How-
ever, mammalian aspartate transcarbamoylase is not reg-
ulated in this manner, and carbamoyl phosphate syn-
thetase II (CPS II) appears to be a primary regula-
tory site. CPS II is inhibited by UTP and is activated
by PRPP and ATP. Activation by ATP may be impor-
tant in achieving a balanced synthesis of purine and
pyrimidine nucleotides. PRPP is also an essential (and
probably a rate-limiting) substrate for the orotate phos-
phoribosyltransferase reaction (reaction 5 in Figure 27-
26) promoting
de novo
pyrimidine nucleotide synthe-
sis by induction of Pyr 1-3. Another potential site of
regulation is orotidine-5-phosphate decarboxylase, which
is inhibited by UMP, CMP, allopurinol nucleotide, and
oxypurinol.
27.10 Coordination of Purine and Pyrimidine
Nucleotide Biosynthesis
A balanced synthesis of pyrimidine and purine nucleotides
is essential for the biosynthesis of nucleic acids in grow-
ing cells. Several mechanisms exist for coordinating nu-
cleotide synthesis.
1. PRPP affects purine and pyrimidine nucleotide
biosynthesis. PRPP formation is activated by
inorganic phosphate and inhibited by several end
products of pathways that use PRPP. In the purine
de novo
pathway, PRPP activates
amidophosphoribosyltransferase and is the
rate-limiting substrate for the enzyme. In purine
