Mechanism of excessive purine biosynthesis in hypoxanthine-guanine phosphoribosyltransferase deficiency

Abstract

A B S T R A C T Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-14C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol.In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-'4C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of '4C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HGPRTase deficiency.

Hypoxanthine-guanine phosphoribosyltransferase: characteristics of the mutant enzyme in erythrocytes from patients with the Lesch-Nyhan syndrome

“…This virtually complete absence of hypoxanthine-guanine phosphoribosyltransferase in patients with the Lesch-Nyhan syndrome has distinguished them from a group of subjects with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (0.03 to 30% of normal) who have gout and hyperuricemia but are without serious neurologic disease (5,14). In the present study, we have found very low but reproducibly detectable levels of hypoxanthine-guanine phosphoribosyltransferase activity in erythrocytes of patients with the Lesch-Nyhan syndrome as have other investigators (15,16). However, the levels of hypoxanthine-guanine phosphoribosyltransferase activity in hemolysates from patients with the Lesch-Nyhan syndrome are still much lower than observed in most patients with gout who have the "partial" enzyme defect.…”

Diagnosis and Treatment of the Lesch-Nyhan Syndrome

“…2). Although levels of activity ranging from 0.2 to 5% of normal have recently been reported in several other patients with the classical syndrome, it is not clear whether the values observed are significantly above background in these particular studies or whether these also represent mutant forms of the enzyme with altered kinetic properties [49,65]. Despite the absence of detectable enzyme activity in hemolysates from most patients with this disease, all examined so far appear to have a protein which exhibits cross reactivity (CRM+) with an antibody to the normal enzyme [2].…”

Dietary-Induced Variation of Hypoxanthine-Guanine Phosphoribosyl Transferase Activity in Patients with the Lesch-Nyhan Syndrome

“…After the initial description of the enzyme defect, several investigators noted low levels of HGPRT activity in hemolysate from patients with this syndrome (2,3) while most found HGPRT activity undetectable (4)(5)(6). More recently we have noted a wide range of HGPRT activity over time in the same patient suggesting that environmental factors might partly account for this discrepancy.…”