Metabolism
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Gout and hyperuricaemia - and anti-cancer drugs
Key points from this exercise:
Uric acid is the end-product of purine catabolism.
Gout is the result of crystallisation of uric acid in joints and as nodules (tophi) under the skin when the plasma concent5ratrion exceeds the solubility limit of uric acid and its salts. Either excessive synthesis of uric acid or defects in its excretion may be the cause.
Plasma uric acid is more or less completely filtered by the glomerulus, but 98% of the uric acid in the glomerular filtrate is reabsorbed in the renal tubules. More distally, there is active secretion of uric acid into the lumen of the tubules. Much of the actively secreted urate is also reabsorbed. A number of compounds inhibit the active secretion of uric acid into the renal tubule.
Premenopausally, women are less at risk of gout than are men; oestrogens enhance the excretion of uric acid.
Precursors of uric acid, and especially xanthine and hypoxanthine, are considerably more soluble that uric acid and its salts. Inhibition of xanthine oxidase therefore provides effective treatment of gout.
The first committed step of de novo purine synthesis is the reaction of phosphoribosyl pyrophosphate (PRPP) with glutamine to form phosphoribosylamine, catalysed by PRPP amidotransferase. This enzyme is subject to allosteric feedback inhibition by AMP and GMP acting synergistically. The Km of PRPP amidotransferase for PRPP is significantly higher than the intracellular concentration of PRPP, so that the activity of the enzyme increases considerably when the intracellular concentration of PRPP rises. This results in increased synthesis of purine nucleotides.
Impaired sensitivity of PRPP amidotransferase to feedback inhibition is a cause of gout in some cases.
Onward metabolism of IMP is inhibited by the end-products of the two branches of the pathway (AMP and GMP)
Two steps in de novo purine synthesis require folic acid derivatives, and folate antimetabolites are effective anti-cancer agents, depriving the tumour cells of purine nucleotides.
Two steps in de novo purine synthesis use glutamine as a nitrogen donor, and glutamine analogues are effective anti-cancer agents, depriving the tumour cells of purine nucleotides.
There is continual catabolism of AMP and GMP, with salvage catalysed by hypoxanthine-guanine phosphoribosyltransferase, in order to maintain appropriate intracellular concentrations of the purine nucleotides.
Mercaptopurine is a synthetic purine analogue that is a substrate for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the enzyme that is involved in purine salvage The product, a purine nucleotide analogue, inhibits all three steps in de novo purine synthesis that are regulated by feedback inhibition.
More or less complete lack of hypoxanthine-guanine phosphoribosyltransferase leads to a considerable increase in the intracellular concentration of PRPP, resulting in increased synthesis of purine nucleotides and hence increased synthesis of uric acid. This is Lesch-Nyhan disease, which leads to gout at an early age as well as severe neurological problems that are the result of developmental defects in dopaminergic neurons.
Partial lack of hypoxanthine-guanine phosphoribosyltransferase is a cause of gout in some people.
For more on Lesch-Nyhan disease, click here or here