ANALYSIS OF ABNORMALITIES IN PURINE METABOLISM LEADING TO GOUT AND TONEUROLOGICAL DYSFUNCTIONS IN MAN

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.