630
chapter 27
Nucleotide Metabolism
U ric acid
(keto form )
P rim ates, birds
uricotelic reptiles,
insects (o th er than
diptera)
Allantoin
A llantoic acid
U re a
A m m o n ia
U rate o xidase
^H20,02
v—CO,
H
H
A llantoicase
лН,о
^ G ly o x y lic acid
О
2H,N— C — NHj
rH p
U re a s e
v.
C O ,
2NH,
M am m a ls (oth er than
prim ates), insects
(dip tera only)
S o m e teleo st fish
M ost fish es, am p h ib ia,
so m e m ollusks
S o m e m arine
in verteb rates,
cru stace an s
F IG U R E 2 7 -1 5
Metabolic degradation of uric acid in some animals.
thiol groups of the enzyme owing to the presence of high
concentrations of oxygen. It is active on purines, aldehy-
des, and pteridines. The reactions catalyzed on purines
are
Hypoxanthine + H20 + 0
2
—> xanthine + H
2
0
2
and
Xanthine + H20 + 0
2
—>
• uric acid + H
2
0
2
The reaction mechanism is incompletely understood.
Molybdenum, an essential cofactor, is the initial accep-
tor of electrons during purine oxidation and undergoes re-
duction from Mo6+ to Mo4+. Deficiency of molybdenum
can result in
xanthinuria.
The electrons from molybde-
num are passed successively to the iron-sulfur center, to
FAD, and finally to oxygen. The oxygen incorporated into
xanthine and uric acid originates in water. Xanthine oxi-
dase also yields the superoxide radical, O-f, which is then
converted to hydrogen peroxide by superoxide dismutase
(Chapter 14). This may yield free radicals,
H
2
0
2
+ Fe2+ -> Fe3+ + OH“ + OH'
which can cause tissue destruction. Thus, the xanthine ox-
idase reaction can cause tissue injury during reperfusion of
organs that have been deprived of oxygen (e.g., ischemic
myocardium, transplanted organs). The xanthine oxidase
reaction is further promoted in hypoxic organs by provid-
ing increased substrates owing to the enhanced adenine
nucleotide breakdown that occurs during oxygen depriva-
tion. Hydrogen peroxide is inactivated by catalase or by
peroxidase. Xanthine oxidase is inhibited by allopurinol
(a purine analogue), which is used in the treatment of gout.
Disorders of Purine Nucleotide Metabolism
Several disorders affect purine metabolism. They are gout
and the syndromes associated with deficiency of HPRT,
APRT, adenosine deaminase, nucleoside phosphorylase,
myoadenylate deaminase, and xanthine oxidase.
Gout
Gout is a heterogeneous group of genetic and acquired dis-
eases characterized by elevated levels of urates in blood
{hyperuricemia)
and of uric acid in urine (
uricuria
). Hy-
peruricemia in men is defined as serum urate concentration
greater than 7 mg/dL (420 /imoI/L) and in women
6
mg/dL
(357 /nmol/L,). In
gout,
hyperuricemia is a common bio-
chemical occurrence; however, many hyperuricemic sub-
jects may not develop clinical gout (asymptomatic hype-
ruricemia). All clinical symptoms of gout arise from the
low solubility of urate in biological fluids. The maximum
solubility of urate in plasma at 37°C is about 7 mg/dL.
However, in peripheral structures and in the extremities,
where the temperature is well below 37°C, the solubility
of urate is decreased. When urate is present in super-
saturated solutions, crystals of monosodium urate mono-
hydrate form easily (Figure 27-16). Deposits of aggre-
gated crystals, known as
tophi,
in and around joints of
OH
H
Monosodium urate
F IG U R E 2 7 -1 6
Structures of tautomeric forms of uric acid. In the lactim form, uric acid has
two acidic hydrogens, with pK' values of 5.75 and 10.3. At physiological
pH (7.4), the predominant species of the lactim form is urate monoanion.
