Adenine phosphoribosyl transferase

Most of the free purines derived from the breakdown of DNA, RNA, and nucleotides in the diet are catabolized to xanthine and then to uric acid in the gut mucosa. The AMP and GMP biosynthesized in the body can also be bmken down to free purines, such as adenine, guanine, and hypoxanthine. These purines, in contrast to those derived frcim the diet, are largely reused for the synthesis of ATP and GTP- They are first converted back to AMP or GMP in a pathway of reutiliza-lion called the purine salvage pathway. For example, adenine phosphoribosyl-transferase (PRPP) catalyzes the conversion of adenine to AMP. Here, PRPP serves as the source of the phosphoribose group. Pyrophosphate is a product of the reaction. 

The phosphoribosyl transferase enzymes catalyze the addition of a ribose 5-phosphate group from PRPP to a free base, generating a nucleotide and pyrophosphate (Fig. 41.12). Two enzymes do this adenine phosphoribosyl transferase (APRT) and hypoxanthine-gnanine phosphoribosyl transferase (HGPRT). The reactions they catalyze are the same, differing only in their substrate specificity. 

M15. Murray, A. W., and Wong, P. C. L., Stimulation of adenine Phosphoribosyl-transferase by adenosine triphosphate and other nucleoside triphosphates. Biochem. J. 104, 669 (1967). 

The base is directly ribosylated with PRPP by PT. The two enzymes concerned with purine salvage are adenine phosphoribosyl transferase (APRT), which catalyzes the formation of AMP, and hypoxanthine-guanine phosphoribosyl transferase (HGPRT), which catalyzes the formation of GMP as well as IMP, the precursor of GMP and AMP (Figure 6.58). Purine nucleotide phosphorylases (PNPases) can also... 

At least three biochemical changes are now established to be part of this disease (1) decreased activity of hypoxanthine guanine phosphoribosyl transferase activity (2) increased levels of PRPP and (3) increased activities of adenine phosphoribosyl transferase. The enzyme defect and increased activity of phosphoribosyl transferase was demonstrated in erythrocytes, skin fibroblasts, liver, and brain tissues of patients. Similarly, high levels of PRPP have been demonstrated in red cells and fibroblasts (4 to 20 times normal). 

The mechanism by which a decrease in activity of the hypoxanthine adenine phosphoribosyl transferase is responsible for the neurological symptoms observed in the Lesch-Nyhan syndrome is not known. At least two possibilities have been proposed. Some portions... 

H. A. Simmonds, J. S. Cameron, M. J. Dillon, T. M. Barratt and K. J. Van Acker. Uric acid stones in children problems of diagnosis and treatment in a new defect - adenine phosphoribosyl-transferase deficiency. Fortschritte der Urol und Nephrol. 16 52 (1981). 

At the present time, we just report some experimental results of a study on the mechanism of action of allopurinol (U-hydroxy-pyrazolo (3, -d ) pyrimidine) and thiopurinol k thiopyrazolo (3, d) pyrimidine) on de novo biosynthesis of uric acid. In this present work, we have compared effect of alio and thiopurinol on oxypurine (xanthine and hypoxanthine) urinary excretion with their rate of synthesis of ribonucleotides in vitro by erythrocyte hemolysate in some particular enzymatic deficiencies (hypoxanthine-guanine phosphoribosyltransferase HGPRT, adenine phosphoribosyl-transferase APRT and xanthinuria). 

Cultured human skin fibroblasts are commonly utilized in the detection of hemizygosity and heterozygosity for hypoxanthine-guanine phosphoribosyltrans-ferase (HGPRT) deficiency. Two obstacles are encountered in the determination of HGPRT and adenine phosphoribosyl-transferase (APRT) in extracts of cultured skin fibroblasts the sensitivity of these enzymes in dilute cell suspension to freezing and thawing (l), and the presence of nucleotidase activity (2). 

Fig. 2. Subunit molecular weight of human adenine phosphoribosyl-transferase (From Thomas, Arnold and Kelley, 1973).

For the past decade this laboratory has devoted much of its attention to an examination of various facets of purine metabolism in human erythrocytes. These cells do not have the complete pathway for the novo synthesis of purines and do not make nucleic acids. On the other hand, they have an active nucleotide metabolism and contain the salvage enzymes, hypoxan-thine-guanine phosphoribosyl transferase (HGPRTase), adenine phosphoribosyl transferase (APRTase) and adenosine kinase. In view of the fact that the activities of certain enzymes of purine metabolism are quite high (e.g., purine nucleoside phos-phorylase occurs at a level of about 15 umolar units/ml of erythrocytes) and the total mass of erythrocytes in the adult human being is in excess of two liters, it appears that these cells play an important and perhaps not yet fully appreciated role in the whole body economy of purines in man. Therefore, we believe that the human erythrocyte provides a very useful model system for the examination of purine metabolism in man as well as for investigations of the action of certain purine and purine nucleoside antimetabolites, many of which are important in medicine. 

Measurements of enzyme activities The enzyme activities of HG-PRT and adenine phosphoribosyl-transferase (A-PRT) of the washed and hemolysed erythrocytes of the test persons were determined according to the radiochemical method of Kelley (3) ... 

RESISTANCE OF ERYTHROCYTE ADENINE PHOSPHORIBOSYL-TRANSFERASE IN THE LESCH-NYHAN SYNDROME TO DESTABILIZATION TO HEAT BY HYPOXANTHINE... 

Fig. 2. Heat inactivation of erythrocyte adenine phosphoribosyl-transferase. The incubation was carried out for eight minutes at 57 C. Results are expressed as percent of control activity in unincubated hemolysate. Control, — , (range in 9 subjects) propositus, (3-0.

Fox, I. H., Meade, J.C. and Kelley, W. N. Adenine phosphoribosyl-transferase deficiency Report of a second family. Amer. J. Med. (in press). 

GOUT WITH ADENINE PHOSPHORIBOSYL TRANSFERASE DEFICIENCY... 

A systematic study of purine phosphoribosyl transferases has led to the discovery of a deficiency of adenine phosphoribosyl transferase (APRT) in a patient with gout and several members of his family, who were either suffering from gout, hyperuricaemia or were normal. 

Screening the purine phosphoribosyl transferases in patients with gout has demonstrated an adenine phosphoribosyl transferase deficiency in one of them. 

Adenine phosphoribosyl transferase deficiency A previously undescribed genetic defect in man. 

Further Evaluation of adenine phosphoribosyl transferase deficiency in man. Occurence in a patient with gout. 

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