Hypoxanthine phosphoribosyl transferase

J3. Jolly, D. J., Okayama, H Berg, P., Esty, A. C., Filpula, D Bohlen, P., Johnson, G. G., Shively, J. E., Hunkapillar, T., and Friedmann, T., Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl-transferase. Proc. Natl. Acad. Sci. U.S.A. 80,477-481 (1983). 

Wu, C. L. and Melton, D. W. Production of a model for Lesch-Nyhan syndrome in hypoxanthine phosphoribosyl-transferase-deficient mice. Nat. Genet. 3 235-240,1993. 

Fig. 14.2 Scheme of thiopurine drug metabolism. HPRT, hypoxanthine phosphoribosyl transferase 6-MMP, 6-methylmercaptopurine 6-TGN, 6-thioguanine nucleotides 6-TIMP, 6-thiosine monophosphate TPMT, thiopurine methyltransferase XO, xanthine oxidase... 

Most cases of hyperuricemia are due to disturbed uric acid excretion via the kidneys (1). A high-purine diet (e.g., meat) may also have unfavorable effects (2). A rare hereditary disease, Lesch-Nyhan syndrome, results from a defect in hypoxanthine phosphoribosyl-transferase (A, enzyme [1]). The impaired recycling of the purine bases caused by this leads to hyperuricemia and severe neurological disorders. 

M Shahabuddin, J Scaife. The gene for hypoxanthine phosphoribosyl transferase of Plasmodium falciparum complements a bacterial HPT mutation. Mol Biochem Parasitol 41 281-288, 1990. 

Fig. 13.2. Synthesis of IMP. c = Hypoxanthine phosphoribosyl transferase (HPRT) GAR = glycinamide ribonucleotide FGAR = formyl glycinamide ribonucleotide PRPP = phosphoribosyl pyrophosphate AICAR = 5 aminoimidazole-4-carboxamide...

Fig. 13.3. Metabolic cooperation between BHK21/C3 cells. Growth of BHK-HPRT-and BHK-TK- cells separately and in mixed (1 1) culture, in medium containing hypoxanthine, aminopterin and thymidine (HAT medium). HPRT = hypoxanthine phosphoribosyl transferase TK = thymidine kinase. (Reproduced from Pitts, 1971, with kind permission of the author and publisher.)...

HAU HECS Hep cells HPRT HSV HTC cells IAA ITES haemagglutinin unit human endothelial cell supernatant human epithelial cells hypoxanthine phosphoribosyl transferase herpes simplex virus hepatoma tissue culture cells indole acetic acid medium supplement containing insulin, transferrin, ethanolamine and selenium... 

Hypoxanthine-guanine phosphoribosyl transferase tAdenine phosphoribosyl transferase... 

Fig. 2 Scheme of thiopurine drug metabolism. 77Wthiopurine methyltransfer-ase, XO xanthine oxidase, HPRT hypoxanthine phosphoribosyl transferase, 6-TIMP 6-thiosine monophosphate, 6-MMP 6-methylmercaptopurine, 6-TGN 6-thioguanine nucleotides, AZA Azathioprine, 6-/WP6-Mercaptopurine... 

FO, which is a Sp2 + Sp2 hybrid, may require frequent recloning Y3 is a rat myeloma, AI2 a human myeloma, the others are from mouse. Drug resistance 8-Ag and 6-Tg 8-azaguanine and 6-thioguanine (cells lack hypoxanthine phosphoribosyl transferase) BUdR S-bromo-2-deoxyuridine (cells lack thymidine kinase). 

It has subsequently been shown that mercaptopurine is first metabolised by the enzyme hypoxanthine phosphoribosyl transferase into thioinosine monophosphate and this then acts as an inhibitor of de novo purine biosynthesis. Mercaptopurine worked even in patients whose leukaemia cells had become resistant to the effects of methotrexate, suggesting that combination chemotherapy with the two drugs might extend the period of remission from disease. The idea of combination chemotherapy to delay induction of resistant strains of microorganisms had, it will be recalled, been suggested by Ehrlich in around 1912. With leukaemia, it was the major breakthrough that was needed to achieve long-term survival in the disease. 

Figure 1 The metabolism of azathioprine and mercaptopurine Key AO, aldehyde ojddase GMPS, guanine monophosphate synthetase HPRT, hypoxanthine phosphoribosyl transferase IMPDH, inosine monophosphate dehydrogenase ITPA, inosine triphosphate pyrophosphohydrolase TPMT, thiopurine methyltransfer-ase XO/XDH, xanthine oxidase/dehydrogenase.

An alternative mechanism of SAB action could involve its known effects on de novo purine biosynthesis (1, S) and/or nucleoside transport (5). The combined inhibitory effects of SAB and purine analogues on purine biosynthesis could result in sufficient depletion of intracellular nucleotide pools to result in enhanced cellular cytotoxicity. In addition, these effects would lead to an increased bioavailability of 5-phosphoribosyl-l-pyrophosphate (PRPP), the first enzymic product in the de novo pathway. Increased PRPP levels would enhance the activity of hypoxanthine phosphoribosyl transferase, leading to increased salvage of purine analogues. 

B. Bakay, C. M. Croce, H. koprowski, and W. L. Nyhan, Restoration of hypoxanthine phosphoribosyl transferase activity in mouse IR cells after fusion with chick-embryo fibroblasts,... 

Ye S.-H. 1993. Hypoxanthine phosphoribosyl transferase assay of lead mutagenicity on keratino-cytes. Zhongguo Yaoli Xuebao 14, 145—147. Cited in Chapter 5, U.S. EPA, 2006. 

Some rare inherited deficiencies of the purine-salvage enzymes hypoxanthine-phosphoribosyl-transferase (HPRT) and adenine-PRT (APRT) lead to primary purine overproduction (Table 20.5). X-linked Lesch-Nyhan syndrome occurs in complete deficiency of HPRT. It is characterized by mental retardation, self-mutilation, choreoathetosis, gout. 

Paraskeva, C., Roberts, C., Briggs, P. and Gallimore, P. H., 1983, Human adenovirus type 2 but not adenovirus type 12 is mutagenic at the hypoxanthine phosphoribosyl transferase locus of cloned rat liver epithelial cells, J. Virol. 46 131. 

It is possible that X chromosome inactivation does not occur along the entire chromosome at the same time. Rather, it occurs gradually and spreads along the chromosome. Observations of the inactivation of one X chromosome during the cultivation of mouse teratocarcinoma cells suggested this. In this case, the reducr tion of G-6-PDH activity as a result of X chromosome inactivation always preceded the reduction of another X-linked enzyme-hypoxanthine phosphoribosyl-transferase. These temporary differences in activity could be caused, however, on the post-transcriptional level as well, as a result of differences in mRNA stability (Martin et al., 1978). 

Two phosphoribosyl transferases then convert adenine to AMP and hypoxanthine and guanine to IMP or GMP (Figure 34-4). A second salvage mechanism involves phosphoryl transfer from ATP to a purine ri-bonucleoside (PuR) ... 

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