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Human Purine Metabolism: Some Recent Advances and Relationships with Immunodeficiency Ann Rheum Dis: first published as 10.1136/ard.42.Suppl_1.8 on 1 January 1983. Downloaded from Ann Rheum Dis (1983), 42, Supplement p 8 Human purine metabolism: some recent advances and relationships with immunodeficiency GEORGE NUKI From the Rheumatic Diseases Unit, Department ofMedicine (WGH), University ofEdinburgh Studies of human purine metabolism 0-6 g (3-6 mmol) while on a 10-9 MJ balanced interaction of several began some 200 years ago with (2600 kilocalorie), 70 g protein, biochemical pathways (Fig. 1). Purine Scheele's identification of uric acid as a purine-free diet is generally taken to biosynthesis de novo consists of a constituent of a renal calculus' and be abnormal,5 but recent data on series of 10 enzymatic steps in which Wollaston's demonstration of urate in healthy Australians on low purine glutamine, glycine, carbon dioxide, a tophus from his own ear.2 Just as diets showed mean urinary urates of aspartate, and 1-carbon-formyl these were among the earliest 3-9 mmol (0 65 g)/24 hrs for men and derivatives of folate are added to the experiments in the new science of 2-9 mmol (0.5 g)/24 hrs for women.6 ribose moiety of phosphoribosyl biochemistry, so Garrod's (1854)3 A variety of mutations of three pyrophosphate (PRPP) to form thread test must rank as the first assay enzymes are associated with excessive inosinic acid (IMP). Adenosine in what we now call the discipline of purine synthesis in patients with gout, monophosphate (AMP) and clinical chemistry. Seegmiller's but these account for only a small guanosine monophosphate (GMP) are discovery, 15 years ago, that the severe proportion of those identified as each formed from IMP by two purine overproduction and gout primary overproducers of urate. enzymatic steps before phosphory- copyright. observed in boys with Lesch-Nyhan Purine nucleotide synthesis in lation to their respective diphosphates syndrome resulted from a specific mammalian cells is regulated by a and triphosphates. Alternatively, the defect of the purine salvage enzyme hypoxanthine-guanine phospho- ribosyl transferase (HGPRT)4 led to Ribose - 5 - P + ATP what has been described as the 'purine revolution' and was soon followed by 5- Phosphoribosyl -1- Pyrophosphate PRPP + Glutamine Deoxynu~cetc Nuclic A * ,Nucleic Dexynucli~c the identification of other inborn Acids Acids ^ Acids Acids errors of dGTPGT* * http://ard.bmj.com/ metabolism associated with dGTP GTP 5-Phosphoibosyl-1-Amine,- AO dAAPAT P : primary purine overproduction and \\ \\\ F?1 ormate 1 /77 gout. Oxypurine and deoxypurine NHCO3 ' Aspartate bases, nucleosides, and nucleotides do, Formate however, have much wider physio- logical importance as intermediates in Guanylic Acd A-rIosindcAcid lo Adeyi Acid Adene d AMP energy metabolism, components of HGPRT ne coenzymes, vasoactive and neuro- Guanosie Io eR Adenosone N transmitter substances, mediators of 9f % 1 > 2,8-dihydroxyademne on September 27, 2021 by guest. Protected hormonal action, and as the building Guanine Hypoxanthine deoxyinosre -i' dexyaadenoswe blocks for transmitters of genetic information (DNA and RNA). Most recently interest has been focused on Xanthine the role of purines, and especially deoxypurines, in the regulation of Uric cid immune responses. Fig. 1 Pathways ofpurine metabolism in man. Gout and hyperuricaemia ADA = Adenosine deaminase. APRT = Adenine phosphoribosyl transferase. In most individuals with gout or HGPRT = Hypoxanthine-guanine phosphoribosyl transferase. asymptomatic hyperuricaemia the rise NP = Nucleoside phosphorylase. in serum urate concentration is the 5'NT = 5'nucleotidase. result of a decrease in renal urate PAT = Phosphoribosyl pyrophosphate amidotransferase. clearance. In 15% or less there is PPRPS = Phosphoribosyl pyrophosphate synthetase. evidence of excessive purine synthesis XO = Xanthine oxidase. and hyperuricosuria. A 24-hour Reproduced from: Nuki G, Advanced Medicine 15. London: Pitman Medical, urinary urate excretion greater than 1979: 140 with permission of publishers. Ann Rheum Dis: first published as 10.1136/ard.42.Suppl_1.8 on 1 January 1983. Downloaded from Human purine metabolism: some recent advances Suppl p 9 nucleotide monophosphates may be the potential regulatory importance of metabolites from uric acid." These synthesised by phosphorylation of the distal inosinic acid branch point." patients may be treated successfully purine bases by phosphoribosyl trans- There is increasing evidence of with a low purine diet and ferase enzymes reacting with PRPP, genetic heterogeneity at the HGPRT allopurinol," which inhibits the and AMP may be formed by locus."2 13 Although the severity of formation of 2,8-dihydroxyadenine. phosphorylation of adenosine by clinical manifestations is usually adenosine kinase. In vitro studies of proportional to the severity of the Superactive PRPP synthetase amido phosphoribosyl transferase enzyme defect, this is not always (PAT), the first enzyme in the de novo apparently the case. In rare instances Structural mutations resulting in pathway, show it to have allosteric mutations resulting in abnormal superactive phosphoribosyl pyro- properties that one often associates enzyme kinetics may be associated on phosphate synthetase are now well with a rate-limiting enzyme, and have the one hand with the classic clinical established as a cause of X-linked gout provided a molecular model for the Lesch-Nyhan phenotype and and purine overproduction. Initially mechanism whereby the rate of purine apparently normal red cell HGPRT increased enzyme activity was associ- nucleotide synthesis may be regulated. activity assayed at saturating substrate ated with decreased sensitivity to The protein exists in two forms; an concentrations, or on the other hand feedback inhibition by purine nucleo- inactive dimer and a catalytically with X-linked gout without tides in one family" and a primary active monomer. PRPP converts the neurological features and apparently increase in catalytic activity per larger form of the enzyme to the active absent enzyme activity in standard enzyme molecule of the mutant pro- monomer, while purine nucleotide assays. Immunochemical studies have tein in another.'4 More recently the monophosphates have the reverse shown that most mutations at the genetic heterogeneity and diversity of effect.7 HGPRT locus are structural gene abnormalities in kinetic mechanisms mutations resulting in catalytically leading to superactivity of this enzyme HGPRT deficiency defective enzyme protein that does not has been extended to include mutants cross react with antibody raised with increased V max, various abnor- In Lesch-Nyhan syndrome and the against highly purified normal human malities of purine nucleotide feedback severe familial form of X-linked gout, HGPRT (CRM negative mutants).'4 inhibitor responsiveness, increased copyright. which is also associated with deficiency Recent studies have provided affinity for the substrate ribose-5- of HGPRT, it seems logical to evidence for a single amino acid phosphate, and a combination of conclude that the considerably substitution in one such structural catalytic and regulatory defects." accelerated rate of de novo purine variant (HGPRTmunich)," while other Most affected males have presented synthesis results from both groups have now succeeded in cloning with gouty arthritis and/or uric acid accumulation of PRPP and diminished the HGPRT gene.' urolithiasis in early adult life, but two feedback inhibition of PAT by purine families have been described where nucleotides. However, while APRT deficiency homozygous boys developed symp- toms in childhood and shared intracellular concentrations of PRPP http://ard.bmj.com/ are increased in HGPRT-deficient Adenine phosphoribosyl transferase metabolic abnormalities and nerve cells, steady state purine nucleotide deficiency is not associated with gout deafness with their heterozygous concentrations do not appear to be or purine overproduction. Although mothers.'6 27 reduced,8 and concentrations of heterozygous, partial APRT pyrimidine nucleotides are actually deficiency was originally described in Type I glycogen storage disease increased.9 A good deal of evidence gouty patients it is clear from family suggests that PRPP, which is present in studies that the enzyme defect and Glucose-6-phosphatase deficiency is cells at limiting concentrations, is the hyperuricaemia are inherited as associated with both overproduction major regulator of rates of de novo independent traits.'8 The apparent and underexcretion of uric acid, so that on September 27, 2021 by guest. Protected purine synthesis whenever purine association arose spuriously because gout and hyperuricaemia become overproduction occurs in vivo. On the APRT enzyme assays were appreciable clinical problems in other hand, the importance of purine undertaken only in patients with gout, affected individuals fortunate enough base 'salvage' is emphasised by although heterozygous APRT to survive to adult life. Persistent lactic experiments which show that rates of deficiency may occur in as many as 1 % acidaemia is the major cause of purine synthesis in normal human of the population.'9 More recently, a impairment of uric acid excretion and lymphoblasts may be increased to number of patients have been the simultaneous increase in de novo those observed in HGPRT-deficient identified in whom severe, purine synthesis observed in these mutants if hypoxanthine is carefully homozygous APRT deficiency was patients is thought to result from excluded from the culture medium."0 associated
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