622
chapter 27
Nucleotide Metabolism
l
-A spartate
_
H
_
O O C — c — c — CO O
H,
H
OOC— c — c — c o o
H
2
4
iNH
NH.
HP
-
/
GTP, Mg +
A denylosuccinate
|
syn th etase
R ibose 5-phosphate
Fum arate
_
H
_
O O C — C = C — CO O
H
A d en ylosu ccin ase
Inosine m onophosphate
(IMP)
R ibose 5-phosphate
A denylsuccinate
(AM PS)
X anthosine m onophosphate
(XMP)
FIGURE 27-9
Biosynthesis of AMP and GMP from IMP.
G uanosine m onophosphate
(GM P)
R ibose 5-phosphate
A d en osin e m onophosphate
(AMP)
adenylic acid (AMP) and guanylic acid (GMP) in two
different pathways (Figure 27-9).
4. All the required enzymes occur in the cytosol. This is
also true for enzymes of salvage pathways, nucleotide
interconversion, and degradation.
5.
De novo
synthesis is particularly active in the liver
and placenta. Nonhepatic tissues (e.g., bone marrow)
depend on preformed purines that are synthesized in
the liver and transported by red blood cells. They are
very effective in salvaging the purines and exhibit
little or no activity of xanthine oxidase, which
oxidizes free purines.
Salvage Pathways
Reutilization of purine bases after conversion to their
respective
nucleotides
constitutes
salvage
pathways.
These pathways are particularly important in extrahepatic
tissues. Purines arise from several sources: intermediary
metabolism of nucleotides, degradation of polynucleo-
tides, and dietary intake. Quantitatively, the first two
sources are the more important. Salvage occurs mainly
by the phosphoribosyltransferase reaction:
Base + PRPP ^ base-ribose-phosphate + PPj
Human tissue contains two phosphoribosyltransferases
(Figure
27-10).
Adenine
phosphoribosyltransferase
(APRT) catalyzes the formation of AMP from ade-
nine. Hypoxanthine guanine phosphoribosyltransferase
(HPRT) catalyzes the formation of IMP and GMP from
hypoxanthine
and
guanine,
respectively.
HPRT also
catalyzes the conversion of other purines (
6
-thiopurine,
8
-azaguanine, allopurinol) to their respective ribonu-
cleotides. The A'eq of both phosphotransferases favors
formation of ribonucleotides. During salvage, only two
high-energy bonds are used, whereas in
de novo
synthesis
of AMP or GMP, at least six high-energy bonds are ex-
pended. Deficiencies of these enzymes are discussed later.
A quantitatively less significant salvage pathway uses
purine nucleoside phosphorylase and nucleoside kinase:
nucleoside phosphoryiase
Base + ribose 1-phosphate <"
>
base-ribose +
P;
nucleoside kinase
Base-nbose +
ATP
-------------
>
base-ribose-phosphate
+
ADP
The phosphorylase can catalyze the formation of ino-
sine or deoxyinosine, and of guanosine or deoxyguano-
sine, but not adenosine or deoxyadenosine. However, the
last two nucleosides can be converted to inosine and de-
oxyinosine by adenosine deaminase. The normal func-
tion of the phosphorylase appears to be the formation
