Hypoxanthine-guanine phosphoribosyltransferase HGPRT

The following reactions are catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

Answer C. The purine antimetabolite 6-mercaptopurine is bioactivated in cancer cells by the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT). The most common form of resistance to 6-MP is a decrease in activity of this enzyme. Azathioprine, a drug used as an immunosuppressant, is closely related to 6-MP and also requires bioactivation to exert cytotoxic actions. 

Thioguanine - selects for cells lacking an active hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Cells containing an active enzyme convert 6-thioguanine to a toxic compound. 

Fig. 5. The effect of allopurinol therapy on erythrocyte orotidylic decarboxylase (ODC), orotate phosphoribosyltransferase (OPRT), hypoxanthine-guanine phosphoribosyltransferase (HGPRT), and adenine phosphoribosyltransferase (APRT), and serum urate in three patients with gout. The upper limits of normal OPRT and ODC activity in erythrocytes (mean 2 S.D.) are indicated by the dotted and solid horizontal lines, respectively. (From Beardmore, Cashman and Kelley, 1972).

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). 

HUMAN HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE (HGPRT) PURIFICATION AND PROPERTIES... 

Human platelets do not synthesize nucleotides de novo (l) but have been demonstrated to possess salvage pathways utilizing adenine and adenosine (2,3). On the other hand, no evidence has been reported as yet for the presence of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in human platelets. 

The Lesch-Nyhan syndrome is a rare, X-linked genetic disease due to a functional absence of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (Seegmiller, Rosenbloom and Kelley, 1967). This enzyme catalyzes the transfer of the 5-phos-phoribosyl moiety of 5-phosphoribosyl-l-pyrophosphate (PP-ribose-P) to the purine bases guanine and hypoxanthine to form the nucleotides inosinic acid and guanylic acid. 

Recent advances in the understanding of human purine metabolism have been stimulated by the discovery of specific inborn errors of this pathway in man. In particular, the demonstration of the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the Lesch-Nyhan syndrome and in some patients with gout has contributed essential information on the regulation of purine biosynthesis novo and on the critical role of this reutilization pathway in central nervous system function in man. The search for other disorders led to the description of a partial deficiency of adenine phosphoribosyltransferase (APRT) in four members in three generations of one family. Each of the subjects partially deficient in APRT exhibited a normal serum urate concentration and the propositus had a normal excretion of uric acid (Kelley, et al., 1968). We have investigated a second family partially deficient in APRT (Fox and Kelley, in press). 

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