Plasma deoxyadenosine, adenosine, and erythrocyte deoxyATP are elevated at birth in an adenosine deaminase-deficient child.

Hirschhorn, Rochelle; Roegner, Vivian; Rubinstein, Arye; Papageorgiou, Photini S.

doi:10.1172/jci109725

Cited by 71 publications

(21 citation statements)

References 18 publications

(22 reference statements)

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Section: Isoenzyme Ada1mentioning

confidence: 99%

“…The isoenzyme ADA1 is also present in red cells, which are equipped with an efficient mechanism to capture and internalize 2'deoxyadenosine. Therefore, in humans, red cells form a "dialysis" system for circulating 2'deoxyadenosine and, in this way, preserve the nucleated cells from an excessive external supply of 2'deoxyadenosine [6].The importance of ADA1 in cells is revealed by the disfunction of the immune response in subjects congenitally lacking ADA1 due to inadequate homeostasis of 2'deoxyadenosine in their immune cells [2,4,6]. There are several other important effects of the substrate adenosine which also bear witness to the importance of the presence of ADA1 in the human body [7]; these will not be discussed here.…”

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confidence: 99%

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Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Gakis¹

1996

Eur Respir J

139

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The isoenzymes ADA1 and ADA2 of the enzyme adenosine deaminase (ADA 3.5.4.4) deaminate mainly two nucleosides: adenosine and 2'deoxyadenosine, producing inosine and 2'deoxyinosine. Adenosine and 2'deoxyadenosine are molecules with many effects on human cells [1][2][3][4]. Thus, the homeostasis of these substances and the activity of the isoenzymes ADA1 and ADA2 in human cells are of extreme importance. Isoenzyme ADA1In humans, the isoenzyme ADA1 is ubiquitous and guarantees the downregulation of the substrates adenosine and 2'deoxyadenosine [1]. This homeostasis is particularly important because a low level of 2'deoxyadenosine is essential for a proper function in immune cells [2][3][4][5]. The isoenzyme ADA1 is also present in red cells, which are equipped with an efficient mechanism to capture and internalize 2'deoxyadenosine. Therefore, in humans, red cells form a "dialysis" system for circulating 2'deoxyadenosine and, in this way, preserve the nucleated cells from an excessive external supply of 2'deoxyadenosine [6].The importance of ADA1 in cells is revealed by the disfunction of the immune response in subjects congenitally lacking ADA1 due to inadequate homeostasis of 2'deoxyadenosine in their immune cells [2,4,6]. There are several other important effects of the substrate adenosine which also bear witness to the importance of the presence of ADA1 in the human body [7]; these will not be discussed here.The Km of ADA1 is 5.2×10 -5 M. ADA1 has an optimal pH of 7-7.5 and a similar affinity for both adenosine and 2'deoxyadenosine (2'deoxyadenosine/adenosine deaminase ratio of 0.75) [1,8].These features make ADA1 highly efficient in deaminating the substrates (adenosine and 2'deoxyadenosine) in biological sites where the pH is optimal for this isoenzyme even though the substrate concentration is very low. Isoenzyme ADA2 (ADA1-ADA2 isoenzymatic system)The isoenzyme ADA2 is not ubiquitous, but coexists with ADA1 only in monocytes-macrophages. ADA2 and ADA1 are coded by different gene loci [1,4,9,10].The Km of ADA2 is 200×l0 -5 M; ADA2 has an optimum pH of 6.5 and a weak affinity for 2'deoxyadenosine (2'deoxyadenosine/adenosine deaminase ratio of 0.25) [1,8,9]. These features make ADA2 inefficient in deaminating 2'deoxyadenosine in biological sites where the pH is higher than the optimum for this isoenzyme and the concentration of substrates is too low.Why, therefore, should ADA2 be present in monocytesmacrophages, where conditions are not suitable for its optimum function? To answer this question, which is extremely important from a biological point of view, it is necessary to consider ADA1 and ADA2 as a system which acts to guarantee the homeostasis of adenosine and 2'deoxyadenosine in monocytes-macrophages. This homeostatic mechanism involves two substrates and two isoenzymes. Both isoenzymes have similar affinity for the substrate adenosine, whilst ADA2 has a different affinity (very weak) for the substrate 2'deoxyadenosine [1,8].Through the simulation model STELLA II (High Performance System Inc., 1993), we h...

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Section: Isoenzyme Ada1mentioning

confidence: 99%

mentioning

confidence: 99%

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Gakis¹

1996

Eur Respir J

139

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“…Consistent with the elevated plasma adenosine and INTRODUCTION Inherited deficiency of the purine salvage enzyme, adenosine deaminase (ADA),' results in the fatal infantile syndrome of severe combined immunodeficiency (ADA-SCID) (1)(2)(3). Affected children accumulate the purine nucleoside substrates of ADA, adenosine, deoxyadenosine, and their phosphorylated metabolites (4)(5)(6)(7)(8)(9)(10)(11)(12). Accumulation of such metabolites presumably results in lymphospecific toxicity, by one or more proposed mechanisms (7,(13)(14)(15)(16)(17).…”

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confidence: 99%

“…The mixture was incubated for 1 h at 37°C and the reaction terminated by addition of 40 gl 2.1 N PCA and neutralized with 40 ul 2.21 N KOH. The supernatant was then analyzed for deoxyadenosine by HPLC on a C18 gBondapak column (9). Preliminary experiments indicated that under these conditions, dAMP, dADP and dATP were totally converted to deoxyadenosine, but that no other reaction products were seen.…”

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Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients.

Hirschhorn¹,

Roegner-Maniscalco²,

Kuritsky³

et al. 1981

J. Clin. Invest.

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A B S T R A C T To delineate the extent to which bone marrow transplantation provides "enzyme replacement therapy", we have determined metabolite concentrations in two patients with adenosine deaminase (ADA) deficiency treated with bone marrow transplants and rendered immunologically normal. 10 yr after engraftment of lymphoid cells, erythrocyte deoxy ATP was markedly decreased compared to the marked elevations of deoxy ATP observed in untreated patients, but was still significantly elevated (62 and 90 vs. normal of6.0+6.0 nmol/ml packed erythrocytes). Similarly, deoxyadenosine and adenosine excretion were both markedly diminished compared to that of untreated patients but deoxyadenosine excretion was still clearly increased (20.1 and 38.6 vs. normal of <0.2 nmol/mg creatinine) while adenosine excretion was in the upper range of normal (7.0 and 8.1 vs. normal of 5.6+3.6 nmol/mg creatinine). Mononuclear cell deoxy ATP content was also elevated compared to normal (5.25 and 14.4 vs. 1.2+0.3). Separated mononuclear cells of bone marrow transplanted patients contain both donor lymphocytes and recipient monocytes. When mononuclear cells were depleted of the patients' own monocytes, the deoxy ATP content of the cells enriched for donor lymphocytes (i.e. monocyte depleted) was lower than that of the mixed mononuclear cells (2.2 vs. 5.26). Surprisingly, plasma adenosine was as high as in untreated ADA-deficient patients (3.2 and 1.5 vs. untreated of 0.3-3 ,uM). Consistent with the elevated plasma adenosine and Portions of this work were presented in part at the 92nd Annual Meeting ofthe Association ofAmerican Physicians and was published in abstract form in

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Five missense mutations at the adenosine deaminase locus (ADA) detected by altered restriction fragments and their frequency in ADA – patients with severe combined immunodeficiency (ADA – SCID)

Hirschhorn¹,

Ellenbogen²,

Tzall³

1992

Am. J. Med. Genet.

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Severe combined immunodeficiency (SCID) is a heterogeneous syndrome, due to X-linked and autosomal recessive defects. A significant proportion of the autosomal recessive forms of SCID are due to mutations at the adenosine deaminase (ADA) locus. Nine different mutations at the ADA locus, including 7 missense point mutations, have been reported in children with ADA-SCID. We could detect 5 of the 7 missense mutations associated with ADA-SCID by alterations in restriction fragments utilizing standard restriction digestion of genomic DNA and hybridization of radiolabelled ADA genomic probes to Southern transfers. We additionally developed more rapid nonradioactive methods employing digestion of genomic DNA amplified by PCR that also detected all 5 mutations. Using these methods, we have examined a sample of 45 ADA-SCID chromosomes and report that these 5 missense mutations account for one third of the ADA--chromosomes studied, with 2 mutations being relatively common.

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Plasma deoxyadenosine, adenosine, and erythrocyte deoxyATP are elevated at birth in an adenosine deaminase-deficient child.

Cited by 71 publications

References 18 publications

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients.

Five missense mutations at the adenosine deaminase locus (ADA) detected by altered restriction fragments and their frequency in ADA – patients with severe combined immunodeficiency (ADA – SCID)

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