Summary
The metabolism of adenosine and its effects on phosphoribosylpyrophosphate, PP-ribose-P, dependent nucleotide synthesis were studied using erythrocytes from patients with adenosine deaminase and hypoxanthine phosphoribosyltransferase deficiency as models. The phosphorylation of adenosine was progressively inhibited by concentrations of adenosine greater than 1 µmol L−1 for control and ADA deficient erythrocytes. There was essentially no initial rate of phosphorylation at 30 µmol L−1 adenosine. Adenosine, 1 µmol L−1, also caused a 60% reduction in PP-ribose-P concentration in ADA deficient erythrocytes. For HPRT deficient erythrocytes in which ADA activity was blocked by coformycin, 10 µmol L−1 inosine stimulated PP-ribose-P dependent nucleotide synthesis from adenine, whereas, 10 µmol L−1 adenosine inhibited nucleotide synthesis. These observations suggest that adenosine phosphorylation and PP-ribose-P dependent nucleotide synthesis are inhibited under conditions in which adenosine accumulates, such as in hereditary or pharmacologically induced ADA deficiency.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agarwal, R. P., Crabtree, G. W., Parks, R. E., Jr., Nelson, J. A., Keightley, R., Parkman, R., Rosen, F. S., Stern, R. C. and Polmar, S. H. Purine nucleoside metabolism in erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency.J. Clin. Invest. 57 (1978) 1025–1035
Cohen, A., Hirschhorn, R., Horowitz, S. D., Rubinstein, A., Polmar, S. H., Hong, R. and Martin, D. W., Jr. Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.Proc. Natl. Acad. Sci. USA 75 (1978) 472–476
Coleman, M. S., Donofrio, J., Hutton, J. J., Hahn, L., Daoud, A., Lampkin, B. and Dyminski, J. Identification and quantitation of adenine deoxynucleotides in erythrocytes of a patient with adenosine deaminase deficiency and severe combined immunodeficiency.J. Biol. Chem. 253 (1978) 1619–1628
Daddona, P. E. and Kelley, W. N. Human adenosine deaminase. Purification and subunit structure.J. Biol. Chem. 252 (1977) 110–115
Donofrio, J., Coleman, M. S., Hutton, J. J., Daoud, A., Lampkin, B. and Dyminski, J. Overproduction of adenine deoxynucleosides and deoxynucleotides in adenosine deaminase deficiency with severe combined immunodeficiency disease.J. Clin. Invest. 62 (1978) 884–887
Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B. and Meuwissen, H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity.Lancet 2 (1972) 1067–1069
Green, H. and Chan, T. S. Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells: role of adenosine deaminase.Science 182 (1973) 836–837
Hawkins, C. F. and Bagnara, A. S. Adenosine kinase from human erythrocytes: kinetic studies and characterization of adenosine binding sites.Biochemistry 26 (1987) 1982–1987
Hawkins, C. F., Kyd, J. M. and Bagnara, A. S. Adenosine metabolism in human erythrocytes: a study of some factors which affect the metabolic fate of adenosine in intact red cellsin vitro.Arch. Biochem. Biophys. 202 (1980) 380–387
Hershfield, M. S., Buckley, R. H., Greenberg, M. L., Melton, A. L., Schiff, R., Hatem, C., Kurtzberg, J., Markert, M. L., Kobayashi, R. H., Kobayashi, A. L. and Abuchowski, A. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase.N. Engl. J. Med. 316 (1987) 589–596
Hershfield, M. S., Kredich, N. M., Ownby, D. R. and Buckley, R.In vivo inactivation of erythrocyteS-adenosylhomocysteine hydrolase by 2′-deoxyadenosine in adenosine deaminase deficient patients.J. Clin. Invest. 63 (1979) 807–811
Hershfield, M. S., Kurtzberg, J., Aiyar, V. N., Suh, E. J. and Schiff, R. Abnormalities inS-adenosylhomocysteine hydrolysis, ATP catabolism, and lymphoid differentiation in adenosine deaminase deficiency. In Tritsch, G. L. (ed.)Adenosine Deaminase in Disorders of Purine Metabolism and in Immune Deficiency, New York Acad. Sciences, 1985, 451, pp. 78–86
Hershfield, M. S., Snyder, F. F. and Seegmiller, J. E. Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage.Science 197 (1977) 1284–1287
Hirschhorn, R. and Roegner, V. Plasma deoxyadenosine, adenosine and erythrocyte deoxy-ATP are elevated at birth in an adenosine deaminase deficient child.J. Clin. Invest. 65 (1980) 768–771
Hutton, J. J., Wiginton, D. A., Coleman, M. S., Fuller, S. A., Limouze, S. and Lampkin, B. C. Biochemical and functional abnormalities in lymphocytes from an adenosine deaminase-deficient patient during enzyme replacement therapy.J. Clin. Invest. 68 (1981) 413–421
Kaukel, E., Fuhrmann, U. and Hilz, H. Divergent action of cAMP and dibutyryl cAMP in macromolecular synthesis in HeLa S3 cultures.Biochem. Biophys. Res. Commun. 48 (1972) 1516–1524
Lukey, T. and Snyder, F. F. Purine ribonucleoside and deoxynucleoside kinase activities in thymocytes. Specificity and optimal assay conditions for phosphorylation.Can. J. Biochem. 58 (1980) 677–682
Lukey, T. and Snyder, F. F.S-adenosylhomocysteine hydrolase activity, deoxyadenosine triphosphate accumulation and competence of thymocyte and spleen leukocyte response to mitogens in coformycin treated mice.Biochem. Pharmacol. 32 (1983) 1399–1406
Miller, R. L., Adamczyk, D. L., Miller, W. H., Koszalka, G. W., Rideout, J. L., Beacham, L. M., Chao, E. Y., Haggerty, J. J., Krenitsky, T. A. and Elion, G. B. Adenosine kinase from rabbit liver. II. Substrate and inhibitor specificity.J. Biol. Chem. 254 (1979) 2346–2352
Mills, G. C., Schmalsteig, F. C., Trimmer, K. B., Goldman, A. S. and Goldblum, R. M. Purine metabolism in adenosine deaminase deficiency.Proc. Natl. Acad. Sci. USA 73 (1976) 2867–2871
Moore, E. C. and Hurlbert, R. B. Regulation of mammalian deoxyribonucleotide biosynthesis by nucleotides as activators and inhibitors.J. Biol. Chem. 241 (1966) 4802–4809
Palella, T. D., Andres, C. M. and Fox, I. H. Human placental adenosine kinase, kinetic mechanism and inhibition.J. Biol. Chem. 255 (1980) 5264–5269
Parker, N. F., Jack, I. and Van der Weyden, M. B. Adenosine and deoxyadenosine-mediated altered pyrimidine metabolism in human adenosine deaminase-deficient lymphoblasts.J. Lab. Clin. Med. 99 (1982) 731–739
Plagemann, P. G. W., Wohlheuter, R. M. and Kraup, M. Adenosine uptake, transport and metabolism in human lymphocytes.J. Cell. Physiol. 125 (1985) 330–336
Planet, G. and Fox, I. H. Inhibition of phosphoribosylpyrophosphate synthesis by purine nucleosides in human erythrocytes.J. Biol. Chem. 251 (1976) 5839–5844
Schmalsteig, F. C., Mills, G. C., Nelson, J. A., May, L. T., Goldman, A. S. and Goldblum, R. M. Limited effect of erythrocyte and plasma infusions in adenosine deaminase deficiency.J. Pediatr. 93 (1978) 597–603
Siaw, M. F. E., Mitchell, B. S., Koller, C. A., Coleman, M. S. and Hutton, J. J. ATP depletion as a consequence of adenosine deaminase inhibition in man.Proc. Natl. Acad. Sci. USA 77 (1980) 6157–6161
Simmonds, H. A., Levinsky, R. J., Perrett, D. and Webster, D. R. Reciprocal relationship between erythrocyte ATP and deoxy-ATP levels in inherited ADA deficiency.Biochem. Pharmacol. 31 (1982a) 947–951
Simmonds, H. A., Webster, D. R., Perrett, D., Reiler, S. and Levinsky, R. J. Formation and degradation of deoxyadenosine nucleotides in inherited adenosine deaminase deficiency.Biosci. Rep. 2 (1982b) 303–314
Smith, C. M., Belch, A. and Henderson, J. F. Hemolysis in mice treated with deoxycoformycin, an inhibitor of adenosine deaminase.Biochem. Pharmacol. 29 (1980) 1209–1210
Snyder, F. F., Hershfield, M. S. and Seegmiller, J. E. Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts.Cancer Res. 38 (1978) 2357–2362
Snyder, F. F. and Lukey, T. Kinetic considerations for the regulation of adenosine and deoxyadenosine metabolism in mouse and human tissues based on a thymocyte model.Biochim. Biophys. Acta 696 (1982) 299–307
Snyder, F. F., Mendelsohn, J. and Seegmiller, J. E. Adenosine metabolism in phytohemagglutinin-stimulated lymphocytes.J. Clin. Invest. 58 (1976) 654–666
Snyder, F. F. and Seegmiller, J. E. The adenosine like effect of exogenous cyclic AMP upon nucleotide and PP-ribose-P concentrations of cultured human lymphoblasts.FEBS Lett. 66 (1976) 102–106
van der Kraan, P. M., van Zandvoort, P. M., De Abreu, R. A., van Baal, J. A. and Bakkern, J. M. Inhibition of lymphoid cell growth by adenine ribonucleotide accumulation. The role of phosphoribosylpyrophosphate-depletion induced pyrimidine starvation.Biochim. Biophys. Acta 927 (1987) 213–221
Wiginton, D. A., Coleman, M. S. and Hutton, J. J. Purification, characterization and radioimmunoassay of adenosine deaminase from human leukaemic granulocytes.Biochem. J. 195 (1981) 389–397
Yamada, Y., Goto, H. and Ogasawara, N. Adenosine kinase from human liver.Biochim. Biophys. Acta 660 (1981) 36–43
Yu, A. L., Bakay, B., Kung, F. H. and Nyhan, W. L. Effects of 2′-deoxycoformycin on the metabolism of purines and the survival of malignant cells in a patient with T-cell leukemia.Cancer Res. 41 (1981) 2677–2682
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Snyder, F.F., Dyer, C., Seegmiller, J.E. et al. Substrate inhibition of adenosine phosphorylation in adenosine deaminase deficiency and adenosine-mediated inhibition of PP-ribose-P dependent nucleotide synthesis in hypoxanthine phosphoribosyltransferase deficient erythrocytes. J Inherit Metab Dis 11, 174–183 (1988). https://doi.org/10.1007/BF01799869
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01799869