Purine Ribonucleoside and Deoxyribonucleoside Metabolism in Thymocytes

Snyder, Floyd F.; Lukey, Trevor

doi:10.1007/978-1-4684-8559-2_42

Cited by 3 publications

(3 citation statements)

References 17 publications

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“…The high ADA/AK ratio will ensure degradation of adenosine. In mu rine thymocytes adenosine and deoxyadeno sine are deaminated predominantly at con centrations ranging from 0.1 to 1,000 \iM [18].…”

Section: Discussionmentioning

confidence: 99%

Age-Dependency of Adenosine Deaminase and Purine Nucleoside Phosphorylase Activities in Rat Spleen and Thymus

Peters¹,

Oosterhof²,

Veerkamp³

1982

Neonatology

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Activities of adenosine deaminase and purine nucleoside phosphorylase were determined in thymocytes and splenocytes of rats of 0–423 days old. Activity of adenosine deaminase per cell is highest in newborn rats and decreases with postnatal development, while in splenocytes adenosine deaminase activity increases. No significant age-dependency is found with purine nucleoside phosphorylase in thymocytes and splenocytes. During whole life adenosine deaminase activity is higher in thymocytes and purine nucleoside phosphorylase activity is higher in splenocytes. With thymocytes, adenosine deaminase activity was higher with deoxyadenosine than with adenosine. The K_m values of both nucleosides were comparable in 3- and 40-day-old rats.

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Section: Discussionmentioning

confidence: 99%

Age-Dependency of Adenosine Deaminase and Purine Nucleoside Phosphorylase Activities in Rat Spleen and Thymus

Peters¹,

Oosterhof²,

Veerkamp³

1982

Neonatology

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“…Adenosine kinase has a lower K M for adenosine than ADA, but in the thymus ADA has a much higher overall activity. Thus, Snyder and Lukey (34) assert that deamination will be favored over phosphorylation in the murine thymus even at adenosine concentrations as low as 100 nM. Our measurements of thymic adenosine levels in normal mice predict that adenosine concentrations will be in the 1.4-M range.…”

Section: Discussionmentioning

confidence: 68%

Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73).

Resta¹,

Hooker²,

Laurent³

et al. 1997

J. Clin. Invest.

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The adenosine producing enzyme ecto-5 Ј -nucleotidase (5 Ј -NT) is not normally expressed during thymocyte development until the medullary stage. To determine whether earlier expression would lead to adenosine accumulation and/or be deleterious for thymocyte maturation, thymic purine metabolism, and T cell differentiation were studied in lck NT transgenic mice overexpressing 5 Ј -NT in cortical thymocytes under the control of the lck proximal promoter. In spite of a 100-fold elevation in thymic 5 Ј -NT activity, transgenic adenosine levels were unchanged and T cell immunity was normal. Inosine, the product of adenosine deamination, was elevated more than twofold, however, indicating that adenosine deaminase (

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“…It is well known that the pathway of dAdo phosphorylation in human thymocytes differs from that in the mouse (17,18), making it essential that models of human thymocyte development be utilized to understand the pathogenesis of ADA deficiency. Despite many early studies, there is still contention regarding which deoxynucleoside kinase is primarily responsible for dAdo phosphorylation in human thymocytes.…”

Section: Introductionmentioning

confidence: 99%

Restoration of Adenosine Deaminase-Deficient Human Thymocyte Development In Vitro by Inhibition of Deoxynucleoside Kinases

Joachims

Marble

Laurent

et al. 2008

The Journal of Immunology

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Mutations in the gene encoding adenosine deaminase (ADA), a purine salvage enzyme, lead to immunodeficiency in humans. Although ADA deficiency has been analyzed in cell culture and murine models, information is lacking concerning its impact on the development of human thymocytes. We have used chimeric human/mouse fetal thymic organ culture to study ADA-deficient human thymocyte development in an “in vivo-like” environment where toxic metabolites accumulate in situ. Inhibition of ADA during human thymocyte development resulted in a severe reduction in cellular expansion as well as impaired differentiation, largely affecting mature thymocyte populations. Thymocyte differentiation was not blocked at a discrete stage; rather, the paucity of mature thymocytes was due to the induction of apoptosis as evidenced by activation of caspases and was accompanied by the accumulation of intracellular dATP. Inhibition of adenosine kinase and deoxycytidine kinase prevented the accumulation of dATP and restored thymocyte differentiation and proliferation. Our work reveals that multiple deoxynucleoside kinases are involved in the phosphorylation of deoxyadenosine when ADA is absent, and suggests an alternate therapeutic strategy for treatment of ADA-deficient patients.

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Purine Ribonucleoside and Deoxyribonucleoside Metabolism in Thymocytes

Cited by 3 publications

References 17 publications

Age-Dependency of Adenosine Deaminase and Purine Nucleoside Phosphorylase Activities in Rat Spleen and Thymus

Age-Dependency of Adenosine Deaminase and Purine Nucleoside Phosphorylase Activities in Rat Spleen and Thymus

Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73).

Restoration of Adenosine Deaminase-Deficient Human Thymocyte Development In Vitro by Inhibition of Deoxynucleoside Kinases

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