Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of adenine deoxynucleotides (dATP and dADP) in the erythrocytes of a patient with adenosine deaminase (ADA) deficiency was confirmed. The patient, now 18 mo old, was treated with a bone marrow transplantation from his HLA identical sister at 7 mo of age. Before and after the transplant, his erythrocyte and lymphocyte ADA activities, as well as his erythrocyte nucleotide profiles, were measured. 10 wk after the marrow transplant, no ADA activity could be detected in his erythrocytes, whereas there was a mixture of donor and patient lymphocytes as measured by ADA assays and karyotyping. At the same time, both dATP and dADP had disappeared from his erythrocytes, which were entirely of patient origin. These findings indicate that partial engraftment of donor lymphocytes into an ADA-deficient patient is capable of "correcting" alterations of deoxynucleotide concentrations in the patient's ADA-deficient erythrocytes.
 ...
PMID:Adenosine deaminase deficiency: disappearance of adenine deoxynucleotides from a patient's erythrocytes after successful marrow transplantation. 37 36

Deoxyadenosine was identified in the urine of a second child with almost undetectable levels of adenosine deaminase (ADA) in erythrocyte lysates. Deoxyadenosine excretion thus appears to be characteristic of ADA deficiency: the acid lability of deoxyadenosine (responsible for the frequent confusion of this abnormal urinary metabolite with adenine) may be used in screening for this defect by isotachophoresis. The deoxynucleotides dATP, dADP and dAMP found initially in the child's erythrocytes (in comparable amounts to ATP, ADP and AMP) disappeared after a successful marrow graft from an unrelated donor, as did the urinary deoxy metabolites. Erythrocyte ADA activity decreased after the marrow graft but was still greater than 10% of normal congruent to 10 weeks after the last red cell transfusion.
 ...
PMID:Purine metabolism in adenosine deaminase deficiency. 38 57

The effect of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy on biochemical abnormalities, clinical status, and immunologic function in an adenosine deaminase-deficient child was investigated. After red cell transfusions, erythrocyte deoxyadenosine triphosphate (dATP) concentrations decreased about 95% and were closely related to adenosine deaminase activities; deoxyadenosine diphosphate concentrations decreased only approximately 30%. The evolution of dATP levels was also closely related to the improvement in clinical status of the patient. However, immune function was not restored. After polyethylene glycol-modified adenosine deaminase therapy, the concentration of erythrocyte dATP decreased to undetectable levels correlated with an increase of T lymphocyte counts and an increase of lymphocyte responses to mitogens. Immune functions were restored only when dATP levels were below 15 mumols/L. It appears that red cell transfusion therapy is not sufficiently effective to reduce and maintain erythrocyte dATP levels at values compatible with normal immune function. On the contrary, polyethylene glycol-modified adenosine deaminase therapy is a suitable treatment to reduce dATP levels to near undetectable values, allowing the immune function to be restored, dATP measurement is a very useful tool for monitoring and evaluating the degree of efficiency of therapy in adenosine deaminase deficiency.
 ...
PMID:Comparison of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy in an adenosine deaminase-deficient child: measurement of erythrocyte deoxyadenosine triphosphate as a useful tool. 239 2

Ordinarily packaged in DNA, adenine deoxyribonucleotides are preferentially concentrated in erythrocyte and lymphocyte cytosol in adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) deficiency. A spectrum of cytosol enzyme activities are defined in terms of reaction velocities, K0.5s, and nucleotide partition after incubation with ribo- and deoxyribonucleotides. AMP and dAMP were dephosphorylated, but only AMP was deaminated in vitro. Although nucleotidase activity is much stronger in lymphocytes, AMP deaminase was the dominant degradative reaction in all erythrocyte and lymphocyte lysates under the conditions specified. For most cytosolic enzymes, ribonucleotides were preferred cofactors, implying that dADP and dATP often may be bystanders at metabolic events. The adenylate kinase-mediated partition of approximately equimolar ribo- and deoxyribonucleotide substrates yielded a very large preponderance of AMP in the monophosphate compartment, the monophosphates alone being directly vulnerable to degradative loss. The adenylate kinase(s) of lymphocytes differed strikingly from those of erythrocytes in reaction velocities with nucleotide cofactors, K0.5s, and in susceptibility to substrate inhibition.
 ...
PMID:Adenine ribo- and deoxyribonucleotide metabolism in human erythrocytes, B- and T-lymphocyte cell lines, and monocyte-macrophages. 386 21

dATP, dADP, and dAMP equalled or exceeded the depleted levels of ATP, ADP, and AMP in erythrocytes from two children with adenosine deaminase (ADA; EC 3.5.4.4) deficiency. dATP and dADP were identified in the mononuclear cells of only one child. The levels of deoxyadenosine compounds fell dramatically after enzyme replacement therapy and were no longer detectable in the urine or in mononuclear cells. Erythrocyte adenosine nucleotide levels showed a corresponding increase. Intact erythrocytes prior to treatment contained adenine, presumed to be from deoxyadenosine degraded during extraction. Adenosine at high concentrations in vitro increased both dATP and ATP levels and decreased intracellular deoxyadenosine levels. There was no significant deamination of either [8-14C]adenosine or deoxyadenosine by intact ADA-deficient erythrocytes. About 90% of adenosine was metabolized to ATP at substrate concentrations from 10-100 microM, compared to 40-60% of deoxyadenosine metabolized to dATP. These studies suggest that (i) high intracellular deoxyadenosine levels may be necessary in vivo to sustain the raised dATP levels in ADA deficiency. (ii) When ADA is inhibited or absent, deoxyadenosine is removed rapidly from the circulation by the human erythrocyte utilizing an adenosine transport system linked to both ADA and adenosine kinase (EC 2.7.1.20).
 ...
PMID:Formation and degradation of deoxyadenosine nucleotides in inherited adenosine deaminase deficiency. 698 23

A reciprocal relationship between erythrocyte ATP and deoxy-ATP levels has been noted in an immunodeficient child with adenosine deaminase (ADA) deficiency during therapy with red cell transfusions. The sum of red cell ATP plus deoxy-ATP equalled the normal complement of ATP prior to any form of therapy. dATP, dADP and dAMP levels were found in the same ratio (10:1:0.1) as the adenine nucleotides ATP, ADP and AMP. Red cell ATP levels were low, not high or normal as found by others in ADA deficiency, but no deoxyadenosine nucleotides could be found in peripheral blood mononuclear cells. Erythrocyte ATP depletion has recently been identified as a serious consequence of anti-leukaemic therapy with ADA inhibitors; it may thus be an important but hitherto unrecognised contributing factor in the clinical expression of inherited ADA deficiency.
 ...
PMID:Reciprocal relationship between erythrocyte ATP and deoxy-ATP levels in inherited ADA deficiency. 708 75