Mechanism of excessive purine biosynthesis in hypoxanthine-guanine phosphoribosyltransferase deficiency.
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-(14)C 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-(14)C 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 (14)C-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 HG-PRTase deficiency.HG-PRTase was not completely absent in red blood cells from a boy with the Lesch-Nyhan syndrome; with hypoxanthine as substrate, the activity in erythrocyte hemolysates was 0.64% of normal values.
D000328:Adult; D000493:Allopurinol / Q000008:administration & dosage; D001264:Athetosis / Q000378:metabolism; D002247:Carbon Isotopes; D002648:Child; D002819:Chorea / Q000378:metabolism; D003192:Compulsive Behavior; D003677:Deficiency Diseases / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D006073:Gout / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D006801:Humans; D007042:Hypoxanthines / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D008607:Intellectual Disability / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000235:genetics; D009705:Nucleosides / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis* / Q000378:metabolism; D012652:Self Mutilation / Q000378:metabolism; D014166:Transferases / Q000378:metabolism*; D014527:Uric Acid / Q000096:biosynthesis / Q000097:blood
D002247:Carbon Isotopes; D007042:Hypoxanthines; D009705:Nucleosides; D011687:Purines; D014527:Uric Acid; D007294:Inositol; D006147:Guanine; D000493:Allopurinol; D014166:Transferases; D005998:Glycine