632
chapter 27
Nucleotide Metabolism
From
g lu co n eo -
g e n e s is _
G ly co g en
l
■
G lu c o se
6
-p h o sp h a te
- ©
G lu c o se
P e n to s e p h o sp h a te
pathway
R ib o se 5 -p h o sp h a te
U
a t p
(D
- - P R P P sy th e ta se
^*AM P
Urinary
uric •
a d d
H ypoxanthine •
G u an in e -
P R P P + G utam ine
l
l
, IM P,
• G M P
‘ A M P -S
I
AM P
H ypoxanthine
• X anthine
(
4
)
Allopurinol
-»inhibits
th e s e s te p s
Uric acid
Enzyme
© G lu c o se -
6
-p h o sp h a ta se
deficiency
Comments
L ea d s to e x c e s s P R P P production
enh an ced ATP turnover
® P R P P sy n th e ta se overactivity
O verproduction of P R P P
(D H yp oxan th in e-guan in e
p h osp h orib osyltran sferase
d e c r e a s e or a b se n c e
D e c r e a se d purine sa lv a g e ; co n v ersio n
of b a s e s to uric acid; en z y m e is com p letely
a b sen t in L esch -N yh an sy n d ro m e
© O verproduction of organic
a d d s
D e c r e a se d secretion of uric acid ow ing to
com petition from other organ ic a cid s
in the kidneys
F IG U R E 2 7 -1 7
Composite diagram of the biochemical lesions that may lead to hyperuricemia.
Acute gouty attacks commonly affect the first metatarsal
joint of the foot. In aspirated joint fluids, birefringent urate
crystals can be seen in the polarized light microscope,
which is used in the definitive diagnosis. The treatment
of acute gout includes the administration of colchicine,
nonsteroidal anti-inflammatory drugs (NS AIDs), corticos-
teroids, adrenocorticotropic hormone (ACTH), and anal-
gesics. Colchicine and NSAIDs also can be used prophy-
lactically to prevent acute attacks in patients with gout.
Drugs used to lower serum urate concentrations include
probenecid, sulfinpyrazone, and allopurinol.
Colchicine
depolymerizes microtubules and structures
(such as the mitotic spindle) consisting of microtubules. It
is effective in decreasing pain and the frequency of attacks
but its mechanism of action is obscure.
Allopurinol,
an analogue of hypoxanthine, inhibits xan-
thine oxidase and reduces formation of xanthine and uric
acid. It is converted by xanthine oxidase to alloxanthine,
which binds tightly to the active site by chelation with
Mo4+. This greatly reduces reoxidation of Mo4+ to Mo6+
and affects catalytic activity (Figure 27-18). This type
of inhibitor, in which a substrate analogue is converted
to an inhibitor and not released from the active site, is
known as a
suicide enzyme-inactivator
or a
mechanism-
based inhibitor
(Chapter
6
). Allopurinol also is converted
to allopurinol ribonucleotide by HPRT. Uric acid produc-
tion is decreased through depletion of PRPP. Allopuri-
nol ribonucleotide also inhibits PRPP-amidotransferase
allosterically. These effects are illustrated in Figure 27-19.
Since xanthine is both a product and a substrate for xan-
thine oxidase, allopurinol therapy could be expected to
cause accumulation of xanthine in the body. Since xan-
thine is only sparingly soluble in urine (but more soluble
than uric acid), this could lead to urinary xanthine crystal-
luria, or stone formation. This complication has not been
observed in patients who receive the drug for treatment of
gout or uric acid stones, but it has occurred in a few pa-
tients with Lesch-Nyhan syndromeand lymphosarcoma.
