Transferase, hypoxanthine

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) ... 

Lesch-Nyhan syndrome, an overproduction hyperuricemia characterized by frequent episodes of uric acid hthiasis and a bizarre syndrome of self-mutilation, reflects a defect in hypoxanthme-guanine phosphoribo-syl transferase, an enzyme of purine salvage (Figure 34—4). The accompanying rise in intracellular PRPP results in purine overproduction. Mutations that decrease or abohsh hypoxanthine-guanine phosphoribosyltrans-ferase activity include deletions, frameshift mutations, base substitutions, and aberrant mRNA splicing. 

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). 

The answer is c. (Katzung, p 933.) Resistance to thioguanine occurs because of an increase in alkaline phosphatase and a decrease in hypoxanthine-guanine phosphoribosyl transferase. These enzymes are responsible, respectively, for the increase in dephosphorylation of thiopurine nucleotide and the conversion of thioguanine to its active form, 6-thioinosinic acid. 

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. 

There was no increase in mutation frequency at the hypoxanthine-guanine phosphoribosyl transferase gene locus in the presence or absence of S9 (Bootman et al. 1988b), and results were negative in a DNA repair assay with E. coli (Hodson-Walker and May 1988). 

Hsie, A.W., Brimer, P.A., Mitchell, T.J. and Gosslee, D.G. (1975). The dos-response relationship for ethyl methane sulfonate-induced mutation at the hypoxanthine-guanine phosphor-ibosyl transferase locus in Chinese hamster ovary cells. Somatic Cell Genet. 1 247-261. 

DNA = Deoxyribonucleic acid HGPRT = hypoxanthine-guanine phosphoribosyl transferase RNA = Ribonucleic acid -= negative result + = positive result (+) = weakly positive result... 

Brimer PA, Tan EL, Hsie AW. 1981. Effect of metabolic activation on the mutagenicity and cytotoxicity of ethylene dibromide in the Chinese hamster ovary hypoxanthine guanine phosphoribosyl transferase [Abstract]. Environ Mutagen 3 317-318. 

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

Patients with Lesch-Nyhan syndrome have hyperuricemia, indicating an increased biosynthesis of purine nucleotides, and markedly decreased levels of hypoxanthine phbs-phoribosyl transferase (HPRT). The hyperuricemia can be explained on the basis of a decrease in which regulator of purine biosynthesis ... 

Answer D. IMP is a feedback inhibitor of PRPP amidophosphoribosyl transferase, the first reaction in the biosynthesis of purines. IMP is formed by the HPRT reaction in the salvage of hypoxanthine. 

Fig. 13.1 Pathways of thiopurine metabolism. The positions of two polymorphically expressed enzymes, TPMT (thiopurine methyl transferase) and ITPA (inosine triphosphate pyrophosphatase), are shown. HGPRT, hypoxanthine guanine phosphoribosyl transferase 6-TIDP, 6-thioi-nosine diphosphate 6-TIMP, 6-thioinosine monophosphate 6-TITP, 6-thio inosine trinophosphate...

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. 

GMP NADH Disappearance GMP Kinase, Pyruvate Kinase, and Lactate Dehydrogenase Hypoxanthine-Guanine Phosphoribosyl-transferase ... 

Rare hereditary deficiency Avoid in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), such as Lesch-Nyhan and Kelley-Seegmiller syndromes. 

Amacher, D.E. Zelljadt, I. (1984) Mutagenic activity of some clastogenic chemicals at the hypoxanthine guanine phosphoribosyl transferase locus of Chinese hamster ovary cells. Mutat. Res., 136, 137-145... 

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