R. Curto et al., ANALYSIS OF ABNORMALITIES IN PURINE METABOLISM LEADING TO GOUT AND TONEUROLOGICAL DYSFUNCTIONS IN MAN, Biochemical journal, 329, 1998, pp. 477-487
A modelling approach is used to analyse diseases associated with purin
e metabolism in man. The specific focus is on deficiencies in two enzy
mes, hypoxanthine:guanine phosphoribosyltransferase and adenylosuccina
te lyase. These deficiencies can lead to a number of symptoms, includi
ng neurological dysfunctions and mental retardation. Although the bioc
hemical mechanisms of dysfunctions associated with adenylosuccinate ly
ase deficiency are not completely understood, there is at least genera
l agreement in the literature about possible causes. Simulations with
our model confirm that accumulation of the two substrates of the enzym
e can lead to significant biochemical imbalance. In hypoxanthine:guani
ne phosphoribosyltransferase deficiency the biochemical mechanisms ass
ociated with neurological dysfunctions are less clear. Model analyses
support some old hypotheses but also suggest new indicators for possib
le causes of neurological dysfunctions associated with this deficiency
. Hypoxanthine:guanine phosphoribosyltransferase deficiency is known t
o cause hyperuricaemia and gout. We compare the relative importance of
this deficiency with other known causes of gout in humans. The analys
is suggests that defects in the excretion of uric acid are more conseq
uential than defects in uric acid synthesis such as hypoxanthine:guani
ne phosphoribosyltransferase deficiency.