Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2',3'-Dideoxyinosine (ddlno) is a potent and selective inhibitor of human immunodeficiency virus in human lymphoid cells and monocytes/macrophages. Earlier studies [J. Biol. Chem. 263:15354 (1988)] showed that anabolism of ddlno in human lymphoid cells is mediated via an initial step of phosphorylation and subsequent amination to dideoxy-AMP via adenylosuccinate synthetase/lyase. Evidence was obtained that neither adenosine kinase nor deoxycytidine kinase is involved in the phosphorylation of this compound in human lymphoid cells. We now find that, in the presence of MgCl2, KCl, and inosine-5'-monophosphate as phosphate donor, purified cytosolic 5'-nucleotidase catalyzed the phosphorylation of ddlno. Although not phosphate donors, ATP, diadenosine tetraphosphate, and glycerate-2,3-bisphosphate stimulate this phosphorylation by the nucleotidase 4-5-fold. In addition to ddlno, the antiviral nucleoside analogs 2',3'-dideoxyguanosine and carbovir were substrates for this enzyme. The relative phosphorylation of these compounds varied with the concentration of the phosphate donor IMP. Approximate Km values of the nucleotidase for inosine, ddlno, dideoxyguanosine, and carbovir were, respectively, 3.4, 0.5, 0.9, and 1.7 mM. Although the substrate activity of dideoxynucleosides is inefficient, it appears likely that this nucleotidase is responsible for the metabolism of these compounds to their active nucleotides, yielding antiviral activity in human lymphoid cells.
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PMID:Phosphorylation of 2',3'-dideoxyinosine by cytosolic 5'-nucleotidase of human lymphoid cells. 254 85

The levels of purine enzyme activities were studied in 10 patients with acquired immunodeficiency syndrome (AIDS) or AIDS related complex (ARC) and in 6 healthy individuals with antibodies against human immunodeficiency virus (HIV). All AIDS/ARC patients studied had ecto-5'nucleotidase (ecto-5'NUC) activity in B lymphocytes below the normal range and 4 out of 6 clinically healthy HIV-positive likewise had reduced activity. Increased numbers of activated B lymphocytes were found both in the group of healthy HIV positive individuals and in AIDS/ARC patients. Further studies are needed to define whether the decrease in ecto-5'NUC activity on the B lymphocytes is a result of increased activation of the cells or of a B cell defect. No significant changes were found in ecto-5'NUC levels in T lymphocytes or mononuclear cells (MNC), neither in the group of AIDS/ARC patients nor in the healthy HIV-positive group. Both AIDS/ARC patients and healthy individuals with antibodies against HIV had increased levels of adenosine deaminase (ADA) activity in mononuclear cells, but only in the group of AIDS/ARC patients was the increase significant. No changes were found in purine nucleoside phosphorylase (PNP) activity in the two groups tested. From these investigations of purine enzyme levels and other markers of immune function in both sick and healthy HIV infected individuals we conclude that the observed changes in ecto-5'NUC and ADA activities in HIV infected patients are not a direct result of the HIV infection but develop early in the course of the disease.
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PMID:Decreased B lymphocyte ecto-5'nucleotidase and increased adenosine deaminase in mononuclear cells from patients infected with human immunodeficiency virus. 284 68

The purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) play an important role in normal lymphocyte differentiation. Abnormal levels of one or all of these enzymes have been associated with immunodeficiency diseases and lymphoproliferative disorders. ADA, PNP, and 5NT activity was measured in peripheral blood T cells from 24 patients with Hodgkin disease (HD) (12 in complete remission and 12 with active disease) to determine whether an association existed between enzyme abnormalities and the decreased cellular immune function previously described in this disorder. HD patients had a significantly decreased absolute lymphocyte count (1,618 +/- 1107/mm3; mean +/- SD) compared to controls (2,320 +/- 980; p less than .001). ADA, PNP, and NT activity was assessed in lymphocyte extracts by measuring the conversion of radiolabeled substrates to products over time. ADA activity expressed as mean +/- SEM nanomoles/10(6) lymphocytes/hr was significantly decreased in T cells from HD patients (84.6 +/- 7.5) compared to controls (128 +/- 12.3; p less than 0.025). Likewise, 5NT was significantly decreased in HD patients (12.7 +/- 1.3) compared to controls (24.0 +/- 3.6; p less than .005). There was not a significant difference in PNP activity between both groups. Low 5NT activity was present irrespective of whether patients had active disease (12.1 +/- 1.5) or were in unmaintained complete remission (14.5 +/- 2.4). These findings suggest that biochemical abnormalities may be responsible for or related to the persistent abnormalities in T-cell function noted throughout the clinical course of HD.
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PMID:Decreased adenosine deaminase (ADA) and 5'nucleotidase (5NT) activity in peripheral blood T cells in Hodgkin disease. 301 Jul 5

The purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) have been shown to be important for normal lymphocyte maturation. Abnormalities of these enzymes have been associated with hereditary as well as acquired immunodeficiency states. Enzyme activity was measured in helper (OKT4) and suppressor (OKT8) lymphocyte subsets from 10 homosexuals with AIDS-related complex (ARC) and in 10 healthy controls. There were no significant differences in either mean ADA activity or mean PNP activity between ARC OKT4 cells and control OKT4 cells and between ARC OKT8 cells and control OKT8 cells. By contrast, mean 5NT activity was slightly decreased in OKT4 cells from ARC patients compared with that of controls and more significantly diminished in ARC OKT8 cells compared with that of controls. Both deoxyadenosine and deoxyguanosine, when incubated separately with OKT4 and OKT8 cells in the presence of EHNA, an ADA inhibitor, did not significantly inhibit lymphocyte blastogenesis to a greater extent in ARC patients than in controls. Hence, the decreases in 5NT activity most likely reflect lymphocyte immaturity and are not associated with biochemical abnormalities leading to increased deoxynucleoside toxicity.
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PMID:Decreased 5'-nucleotidase activity in suppressor (OKT8) T lymphocytes from homosexuals with AIDS-related complex: nonassociation with enhanced deoxynucleoside toxicity. 302 91

It has been recently demonstrated that ecto-5'nucleotidase (5'NT) activity is significantly decreased in the peripheral blood lymphocytes (PBL) of homosexual men. This paper reports a study of PBL 5'NT activity in 38 hemophiliacs at risk for the acquired immunodeficiency syndrome (AIDS). The enzyme activity was correlated to the immunologic and virologic data. T-cell subset distribution was unbalanced and directly correlated with the cumulative amount of AHF infused. PBL 5'NT activity, however, was similar to that of healthy controls. 6 patients displayed serum antibodies to the human immunodeficiency virus (HIV) but no decrease in PBL 5'NT activity. In conclusion, these data indicate that both heavily treated and seropositive as well as untreated hemophiliacs have normal PBL 5'NT activity. This striking dissimilarity between homosexual men and hemophiliacs suggests that some immunologic alterations leading to 5'NT deficiency occur in the former only.
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PMID:Immunologic and virologic findings in hemophiliacs do not correlate with ecto-5'nucleotidase activity of peripheral blood lymphocytes. A difference with homosexual men. 303

The maturing reticulocyte degrades ribosomal RNA to constituent ribonucleoside phosphates. Guanosine ribonucleotides are retained only in small amounts and pyrimidine ribonucleotides only in trace quantities. In the mature erythrocyte more than 97% of total nucleotides are the interconvertible adenosine mono-, di-, and triphosphates. High energy ATP fuels most of the reactions required to sustain viability. Unable to synthesize adenosine phosphates from small precursor molecules, the red cell relies on certain salvage pathways to replenish its losses from the adenosine phosphate pool. The most important of these involve adenosine. Adenylate kinase deficiency, when severe, is associated with nonspherocytic hemolytic anemia. A genetically-determined deficiency of pyrimidine 5'-nucleotidase prevents the normal dephosphorylation of pyrimidine ribonucleotides, and hence is characterized by the unique accumulation of pyrimidine phosphates intracellularly. Other features are chronic hemolytic anemia, splenomegaly, and a profound increase in basophilic stippling on the stained blood film. The syndrome is transmitted as an autosomal recessive disorder. A similar syndrome is found in severe lead poisoning as a consequence of nucleotidase inhibition by lead. An inherited, dominantly transmitted hemolytic anemia associated with low red cell ATP and a 45-70 fold increase in the enzymatic activity of adenosine deaminase has also been documented. The undefined molecular lesion appears to involve overproduction of an entirely normal enzyme protein. Severe deficiency of either of two sequential enzymes of purine metabolism, adenosine deaminase anemia, but by excessive accumulations of deoxyribonucleotides within red cells and lymphocytes. The clinical counterpart of each is a severe immunodeficiency state secondary to lymphopenia and lymphocyte dysfunction. Certain other rare clinical syndromes involving disturbed nucleotide metabolism also are detectable by red cell assay procedures.
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PMID:Erythrocyte disorders of purine and pyrimidine metabolism. 625 19

Microanalysis of subcellular organelle marker enzymes was applied to cryopreserved lymphocytes (obtained and processed in the field) from East African blacks with moderate to severe malnutrition and subject to locally endemic parasitic and infectious diseases. An initial study demonstrated that activities of these enzymes, with the partial exception of catalase, were stable to cryopreservation. Cryopreserved and thawed lymphocyte specimens (1 to 3 X 10(6) viable cells) from 26 Africans and 20 Caucasian controls were studied. There was a highly significant decrease in 5'nucleotidase activity in these African subjects. Activity of another plasma membrane enzyme, gamma-glutamyl transferase, and of marker enzymes for other intracellular organelles, was not significantly different between the two groups, indicating that the nucleotidase alteration is highly specific. 5'Nucleotidase activity in a group of 17 East African blacks of high socio-economic status lay between the values obtained in the other two groups and was not significantly different from either. Further studies on 5'nucleotidase showed no evidence that the enzyme is functionally different in Africans. The differences in activity of this enzyme in Africans may reflect the known immuno-suppressive effects of infectious disease and malnutrition or may have a genetic basis which may in turn be associated with the pathogenesis of secondary immunodeficiency.
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PMID:Lymphocyte enzyme activities in East African blacks: decrease in 5'nucleotidase and possible relation to immunosuppression. 632 May 6