Abstract
Deoxypurine metabolism in human thymocytes and mature T lymphocytes differs remarkably from other cell types (1–3). When the normal pathways of deoxyadenosine and deoxyguanosine degradation are lacking in adenosine deaminase (ADA) and purine nucleoside Phosphorylase (PNP) deficient patients, human T cells exposed to even micromolar concentrations of the respective nucleosides progressively accumulate dATP or dGTP intracellularly. The dATP and dGTP increase to toxic levels primarily in this cell type because(i) in T cells deoxynucleoside phosphorylating activity substantially exceeds deoxynucleotide dephosphorylating activity, and (ii) nucleotides, as opposed to nucleosides, do not readily traverse cell membranes, and hence are trapped intracellularly.
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References
D. A. Carson, E. Lakow, D. B. Wasson, and N. Kamatani, Lymphocyte dysfunction caused by deficiencies in purine metabolism, Immunol. Today 2: 234 (1981).
D. A. Carson, J. Kaye, S. Matsumoto, J. E. Seegmiller, and L. Thompson, Biochemical basis for the enhanced susceptibility of human malignant T cell lines to deoxyribonucleosides, Proc. Natl. Acad. Sci. USA 76: 2430 (1979).
D. A. Carson, J. Faze, and D. B. Wasson, Differences in deoxy-adenosine metabolism in human and mouse lymphocytes, J. Immunol, 124: 8 (1980).
D. A. Carson, J. Kaye, and J. E. Seegmiller, Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside Phosphorylase deficiency. Possible role of nucleoside kinase(s), Proc. Natl. Acad. Sci. USA 74: 5677 (1977).
M. S. Hershfield, and N. M. Kredich, Resistance of an adenosine kinase deficient human lymphoblastoid cell line to effects of deoxyadenosine or growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation, Proc. Natl. Acad. Sci. USA 77: 4292 (1980).
M. S. Hershfield, J. E. Fetter, W. C. Small, A. S. Bagnara, S. R. Williams, B. Ullman, D. W. Martin, Jr., D. B. Wasson, and D. A. Carson, Effects of mutational loss of adenosine kinase and deoxycytidine kinase on deoxy-ATP accumulation and deoxyadenosine toxicity in cultured CEM human T lymphoblastoid cells, J. Biol. Chem., in press (1982).
D. A. Carson, J. Kaye, and D. B. Wasson, The potential importance of soluble deoxynucleotidase in mediating deoxyadenosine toxicity in human lymphoblasts, J. Immunol. 126: 348 (1981).
D. A. Carson, E. Lakow, D. B. Wasson, and N. Kamatani, Possible metabolic basis for the different immunodeficient states associated with genetic deficiencies of adenosine deaminase and purine nucleoside Phosphorylase, Proc. Natl. Acad. Sci. USA, in press (1982).
R. Itoh, Purification and properties of cytosol 5′-nucleotidase from rat liver, Biochim. Biophys. Acta 657: 402 (1981)
D. A, Carson, and D. B. Wasson, Characterization of an ATP and dATP activated nucleotidase from human malignant lymphocytes. Submitted for publication.
D. W. Martin, Jr., and E. W. Gelfand, Biochemistry of diseases and immunodevelopment, Ann. Rev, Biochem. 50: 845 (1981).
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Carson, D.A., Wasson, D.B., Lakow, E., Kamatani, N. (1984). Biochemical Basis for Lymphocyte Dysfunction in Adenosine Deaminase and Purine Nucleoside Phosphorylase Deficiencies. In: De Bruyn, C.H.M.M., Simmonds, H.A., Müller, M.M. (eds) Purine Metabolism in Man-IV. Advances in Experimental Medicine and Biology, vol 165. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-0390-0_27
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DOI: https://doi.org/10.1007/978-1-4757-0390-0_27
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