adenosine monophosphate (AMP) and GMP are generated from the dephos-
phorylation of ATP and GTP, respectively. AMP is then deaminated to IMP by
AMP deaminase. Subsequently, GMP and IMP are dephosphorylated by spe-
cific nucleotidases to produce the nucleosides inosine and guanosine.
Alternatively, AMP can be dephosphorylated to form adenosine, which is then
deaminated by adenosine deaminase (ADA) to form inosine. Inosine and
guanosine are further broken down by the cleavage of the purine base from the
ribose sugar to yield ribose 1-phosphate and hypoxanthine and guanine,
respectively. Similar reactions are carried out for the degradation of purine
deoxyribonucleotides and deoxyribonucleosides. Guanine is deaminated to
form xanthine, whereas hypoxanthine is oxidized to form xanthine by the
enzyme xanthine oxidase. Xanthine is further oxidized, again by xanthine oxi-
dase, to form uric acid, which is excreted in the urine. Uric acid has a pKa of
5.4 and is in the ionized urate form at physiologic pH. Urate is not very solu-
ble in an aqueous environment and the concentration of urate in human blood
is very close to saturation. Therefore, conditions that lead to excessive degra-
dation of purine bases can lead to the formation of urate crystals.
Metabolic abnormalities that lead to the overproduction of purine
nucleotides through the
de novo
pathway lead to increased purine degradation
and subsequent hyperuricemia. An example of this is an increase in the activity
of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase. This enzyme is
responsible for the production of PRPP, which is an important precursor of both
purine and pyrimidine de novo biosynthesis. Elevations in PRPP lead to
increased purine nucleotide production that can in turn increase the rate of degra-
dation and hence increased uric acid production. Hyperuricemia can also result
from defects in the purine salvage pathway. The enzyme hypoxanthine-guanine
phosphoribosyltransferase (HGPRT) is responsible for reforming IMP and GMP
from hypoxanthine and guanine, respectively. In this manner purine bases are
salvaged back into the purine nucleotide pool. Lesch-Nyhan syndrome results
from an inherited deficiency in HGPRT. This syndrome is associated with men-
tal retardation and self-destructive behavior, which may be associated with inad-
equate production of purine nucleotides through the salvage pathway in certain
neuronal cells. In addition, Lesch-Nyhan patients have gout resulting from the
inability to salvage purine bases, which leads to increased levels of uric acid.
Hyperuricemia and gout can also arise from numerous undefined mechanisms
that include dietary issues.
One approach for the treatment of gout is to decrease the production of uric
acid to prevent the development of urate crystals. Allopurinol is an inhibitor
of xanthine oxidase enzymatic activity (see Figure 43-1). The administration of
allopurinol is an effective treatment of gout because it decreases the amount
of uric acid produced, which in turn alleviates the amount of sodium urate
crystals that are formed. Additional drugs used for the treatment of gout
include alloxanthine, another inhibitor of xanthine oxidase, and colchicine,
which inhibits microtubule formation and prevents phagocytic cells from
engulfing the urate crystals. This prevents the urate crystals from rupturing
the phagocytes and causing inflammation in the joints.
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