section 27.8
Catabolism of Purine Nucleotides
H ypoxanthine
Serum urate levels can be lowered by dietary and
lifestyle changes. These include correction of obesity,
avoidance of ethanol consumption, and avoidance of high-
purine foods (e.g., organ meats). Psuedogout is a disorder
caused by deposition of calcium pyrophosphate dihydrate
usually in larger joints such as knee, wrist, and ankle.
X anthine
o x id a se
F IG U R E 2 7 -1 8
Inhibition of xanthine oxidase by allopurinol, an analogue of hypoxanthine.
N7 and C
of hypoxanthine are reversed in allopurinol. Allopurinol, a
suicide enzyme inactivator, is converted to alloxanthine, which binds
tightly to the active site of the enzyme via Mo4+ and interrupts the
reoxidation of Mo4+ to Mo6+ needed to initiate the next catalytic cycle.
Drugs that increase uric acid excretion in humans in-
which is effective in the regulation
of hyperuricemia and the resolution and prevention of
tophi, and
which has similar effects.
Both agents are weak organic acids and probably act
as competitive inhibitors of tubular reabsorption of uric
A lloxanthine (su icid e e n z y m e -
inactivator o f xan th in e o x id a se)
D e p le te s th e
su p p ly of P R P P
n e e d e d for the
first ste p of
d e n ovo purine
n u cleotid e
b io sy n th esis
Allopurinol ribonucleotide
Inhibits th e first ste p of
d e novo purine nucleotide
b io sy n th esis
F IG U R E 2 7 -1 9
Multiple actions of allopurinol inhibit formation of uric acid.
Lesch-Nyhan Syndrome
Lesch-Nyhan syndrome is characterized by virtual ab-
sence of HPRT, excessive production of uric acid, and
abnormalities of the central nervous system. These abnor-
malities include mental retardation, spasticity (increased
muscle tension resulting in continuous increase of resis-
tance to stretching), choreoathetosis (characterized by ir-
regular, jerky, or explosive involuntary movements, and
writhing or squirming, which may involve any extremity or
the trunk), and a compulsive form of self-mutilation. The
disorder associated with partial deficiency of HPRT also
leads to hyperuricemia but lacks the devastating neurolog-
ical and behavioral features characteristic of the Lesch-
Nyhan syndrome. Both disorders are X-linked.
The hyperuricemia in Lesch-Nyhan patients is ex-
plained, at least in part, on the basis of intracellular accu-
mulation of PRPP leading to increased purine nucleotide
de novo
and increased production of uric acid.
Such patients do not usually develop gouty arthritis early
in life but do exhibit uric acid crystalluria and stone for-
In Lesch-Nyhan patients, all tissues are devoid of HPRT.
The disorder thus can be detected by an assay for HPRT
in erythrocytes and by cultured fibroblasts. The former
test has been used in detection of the heterozygous state.
HPRT is a 217-amino-acid cytosolic enzyme coded for by
a single gene on the X chromosome.
Several mutations of the HPRT gene are known
(Table 27-2). Mutations include major gene alterations and
missense mutations causing either gouty arthritis or Lesch-
Nyhan syndrome (Table 27-2). An example of a mis-
sense mutation causing Lesch-Nyhan syndrome is HPRT-
Kinston, which has a substitution of asparagine for aspartic
acid at position 194 (D194N). The mutant enzyme, al-
though present in a concentration similar to that of the
normal enzyme, is catalytically incompetent because of
its very high
values for hypoxanthine and PRPP.
The mechanism by which deficiency of HPRT causes
central nervous
system disorders remains unknown.
Lesch-Nyhan patients do not show anatomical abnormal-
ities in the brain. In normal subjects, HPRT activity is
high in the brain and, in particular, in the basal ganglia
de novo
purine biosynthesis is low. This suggests
the importance of the purine salvage pathway in this tissue.
However, the relationship between HPRT deficiency and
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