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• W2937613318 abstract "The literature relating to mutant enzymes in purine metabolism has been reviewed with particular reference to deficiencies of adenine phosphoribosyltransferase (APRT, E.C. 2.4.2.7) and hypoxanthineguanine phosphoribosyltransferase (HGPRT, E.C. 2.4.2.8). While the metabolic and clinical significance of APRT mutations is in question, mutations of HGPRT are significant, not only metabolically and clinically, but also in relation to the Lyon hypothesis of random inactivation of the X-chromosome in females. Several lines of investigation have been pursued with the aim of elucidating possible connections between the enzyme mutations and their metabolic and clinical consequences.1. Spectrophotometric assaysNovel spectrophotometric assays for APRT and HGPRT have been developed in which the absorbance of the residual purine base is measured after nucleotide product and haemolysate proteins have been simultaneously rerooved by adsorption onto a gelatinous lanthanum phosphate precipitate. These assays are simpler, quicker and less expensive than the standard radiochemical assays currently in use. The spectrophotometric assay for HGPRT should prove particularly useful as a screening procedure for HGPRT deficiency in clinical laboratories not equipped for radiochemical techniques.2. APRT deficiencyThe novel spectrophotometric assay for APRT has been used here to measure haemolysate APRT activity in seven hundred nonnal blood donors in order to detennine the incidence of APRT deficiency in the normal population. Three clearly deficient individuals were found whose APRT activity was lower than three standard deviations below the mean. This is an incidence of 0.4%, which is not significantly different (Fisher exact test) from an incidence of two APRT deficient subjects in 85 patients with gout studied in this laboratory. Thus the apparent connection between APRT deficiency and disordered purine metabolism, observed in a number of laboratories, is most likely a selection artefact since most APRT assays have hitherto been undertaken in the gouty population. Consistent with this conclusion, phosphoribo-sylpyrophosphate concentrations have been measured in erythrocytes and fibroblasts from several APRT deficient subjects and found to be within the nonnal range. APRT activity and the rate of purine synthesis de novo, measured in fibroblasts from these subjects, also appear to be nonnal. These studies indicate that there is no aetiological connection between APRT deficiency in erythrocytes and disorders of urate metabolism.3. HGPRT deficiencyAn autoradiographic technique for demonstrating HGPRT activity in individual erythrocytes has been developed which can distinguish HGPRT+ from HGPRT- cells. With this technique, the occurrence of two cell populations, predicted by the Lyon hypothesis, has been directly demonstrated in erythrocytes from heterozygotes in two families with moderate HGPRT deficiency. By contrast, two heterozygotes from a family with severe HGPRT deficiency (Lesch-Nyhan syndrome), have been shown to have only a single population of nonnal cells. In a third family, with the least severe fonn of HGPRT deficiency (0.1% of nonnal activity), either a deficient or a nonnal pattern of autoradiographic labelling of the cells could be obtained by varying the incubation conditions. This indicates that changing environmental factors can elicit a differential response from HGPRT- cells, depending on the severity of the enzyme deficiency. These results suggest that, whereas there is a wide spectrum of severity of HGPRT deficiency, there is a critical intracellular level of HGPRT activity which, in the hemizygote, leads to the Lesch-Nyhan syndrome, and which, in the heterozygote, results on their own (in the hemizygote) and also in competition with normalcells (in the heterozygote).4. Inhibitors of HGPRTAttempts have been made to produce an inhibitor of HGPRT which might be used as an in vivo inactivating agent to create animal models of HGPRT deficiency. Several 8-substituted derivatives of guanine were synthesised but none of these was significantly inhibitory. Attempts to produce 9-substituted derivatives by periodate oxidation of guanosine, resulted initially in two distinct inhibitors of the enzyme. One of these, guanosine dialdehyde, was found to be a relatively specific inhibitor of HGPRT. In the presence of magnesium phosphoribosylpyrophosphate, guanosine dialdehyde acts as a reversible inhibitor of the enzyme, exhibiting non-competitive kinetics with respect to each of the substrates. In the absence of magnesium phosphoribosylpyrophosphate, the inhibitor irreversibly inactivates the enzyme, showing saturation kinetics. APRT and nucleoside phosphorylase are not significantly inhibited by guanosine dialdehyde. Adenosine dialdehyde, the periodate oxidation product of adenosine, has no effect on HGPRT even though it substantially inhibits APRT. This relatively specific interaction between guanosine dialdehyde and HGPRT is superimposed on, and partly obscured by, non-specific interactions between the inhibitor and other proteins. Although these non-specific effects render guanosine dialdehyde unsuitable for use in vivo, the results suggest that further modification of the ribose moiety of guanosine may be a fruitful approach to the development of an in vivo inhibitor of HGPRT." @default.
• W2937613318 created "2019-04-25" @default.
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• W2937613318 date "2019-03-18" @default.
• W2937613318 modified "2023-09-28" @default.
• W2937613318 title "Mutational deficiencies of the purine salvage enzymes, adenine phosphoribosyl-transferase and hypoxanthine-guanine phosphoribosyltransferase : laboratory studies" @default.
• W2937613318 doi "https://doi.org/10.14264/uql.2019.165" @default.
• W2937613318 hasPublicationYear "2019" @default.
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