Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In paroxysmal nocturnal hemoglobinuria (PNH), infection, both viral and bacterial, disproportionate to the mild neutropenia seen in many such patients is responsible for significant morbidity. We report impaired granulocyte chemotaxis efficiency which may contribute to the problems induced by bacterial infections. PNH (but not normal) granulocytes, after exposure to very small concentrations of activated serum complement components, migrate poorly, as documented by their inhibited chemotaxis toward bacterial products or activated complement components in Boyden chambers. The granulocytes remain intact, excluding trypan blue, phagocytosing, and killing bacteria, despite this activated complement exposure. It is also suggested that this chemotactic defect may involve only a clone of cells, analogous to the clonal lysis of PNH erythrocytes; those few granulocytes capable of migration after exposure to activated complement contain normal quantities of leukocyte alkaline phosphatase (LAP), in contrast to the LAP deficiency of the overall PNH granulocyte population. Since bacterial infection may initiate or potentiate hemolysis, one of the major symptoms of the disease, these results could explain much of the morbidity of PNH.
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PMID:Complement-mediated granulocyte dysfunction in paroxysmal nocturnal hemoglobinuria. 127 74

Many proteins of eukaryotic cells are anchored to membranes by covalent linkage to glycosyl-phosphatidylinositol (GPI). These proteins lack a transmembrane domain, have no cytoplasmic tail, and are, therefore, located exclusively on the extracellular side of the plasma membrane. GPI-anchored proteins form a diverse family of molecules that includes membrane-associated enzymes, adhesion molecules, activation antigens, differentiation markers, protozoan coat components, and other miscellaneous glycoproteins. In the kidney, several GPI-anchored proteins have been identified, including uromodulin (Tamm-Horsfall glycoprotein), carbonic anhydrase type IV, alkaline phosphatase, Thy-1, BP-3, aminopeptidase P, and dipeptidylpeptidase. GPI-anchored proteins can be released from membranes with specific phospholipases and can be recovered from the detergent-insoluble pellet after Triton X-114 treatment of membranes. All GPI-anchored proteins are initially synthesized with a transmembrane anchor, but after translocation across the membrane of the endoplasmic reticulum, the ecto-domain of the protein is cleaved and covalently linked to a preformed GPI anchor by a specific transamidase enzyme. Although it remains obscure why so many proteins are endowed with a GPI anchor, the presence of a GPI anchor does confer some functional characteristics to proteins: (1) it is a strong apical targeting signal in polarized epithelial cells; (2) GPI-anchored proteins do not cluster into clathrin-coated pits but instead are concentrated into specialized lipid domains in the membrane, including so-called smooth pinocytotic vesicles, or caveoli; (3) GPI-anchored proteins can act as activation antigens in the immune system; (4) when the GPI anchor is cleaved by PI-phospholipase C or PI-phospholipase D, second messengers for signal transduction may be generated; (5) the GPI anchor can modulate antigen presentation by major histocompatibility complex molecules. Finally, at least one human disease, paroxysmal nocturnal hemoglobinuria, is a result of defective GPI anchor addition to plasma membrane proteins.
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PMID:Glycosyl-phosphatidylinositol-anchored membrane proteins. 145 Mar 66

Decay-accelerating factor (DAF), a complement-regulating glycoprotein, was found to be a maturational protein for normal neutrophils, and a remarkable correlation was found between the DAF level and alkaline phosphatase activity in neutrophils. We studied the relationship between the amount of DAF on the membrane and cell maturity in total nucleated bone marrow (BM) cells, mature BM and peripheral blood (PB) neutrophils from normal subjects, and patients with paroxysmal nocturnal hemoglobinuria (PNH) using a fluorescence-activated cell sorter with anti-DAF monoclonal antibodies. Percentage distributions of differentiating neutrophils from normal total nucleated BM cells showed that the proportion of immature cells (myeloblasts plus promyelocytes) decreased, while that of mature ones (bands plus segmented forms) increased as the fluorescence intensity increased. For PB neutrophils, no apparent correlation was found between DAF expression and cell maturity. This may have resulted from margination of the fully matured neutrophils with a high amount of DAF. In PNH patients who have low levels of DAF, this study showed that DAF expression in their neutrophils differs from that in normal subjects, and abnormalities occur in PNH cells from a very early stem-cell stage.
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PMID:Membrane expression of decay-accelerating factor on neutrophils from normal individuals and patients with paroxysmal nocturnal hemoglobinuria. 168 98

Paroxysmal nocturnal hemoglobinuria, first described in the late 19th century, is an acquired disorder characterized by hemoglobinemia and hemoglobinuria. The major clinical manifestation of PNH is chronic intravascular hemolysis of various severity. Patients-mostly young adults - may also present with episodes of abdominal or back pain. Common cause of death is thrombosis especially of the hepatic veins. Granulocytopenia and thrombocytopenia may be the initial manifestation of PNH, indicating that the disorder is a primary bone-marrow disease, affecting not only the erythrocytes but also other peripheral blood cells and the haematopoietic stem cell. The course of the disease is variable. Partial complete recovery was described, but also fatal thrombosis. The major phenotypic expression of PNH is an increased susceptibility of the erythrocytes to the lytic action of complement in vitro. The enhanced complement susceptibility is most probably due to membrane defects: two membrane proteins regulating the complement cascade in PNH cells were missing, the decay-accelerating factor, DAF, inhibiting the activation of the lytic complement complex and the C8 binding protein, C8bp, which interferes with the lytic process. Aside from the lack of the complement regulators also other membrane defects have been described (e.g. of acetylcholinesterase or alkaline phosphatase). The proteins as well as DAF and C8bp are linked to the cell membrane via a phosphatidylinositol (PI) anchor, leading to the speculation that the disease results from a deficiency in the post-translational PI anchoring mechanism. The diagnosis of PNH is based on the Hamtest, but will be extended to the quantitation of the above described membrane proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Paroxysmal nocturnal hemoglobinuria]. 218 38

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder in which the blood cells demonstrate aberrant interactions with serum complement. In part, this is due to the absence of the complement regulatory protein, decay accelerating factor (DAF). A small number of patients with PNH have gone on to develop acute nonlymphocytic leukemia, which is thought to arise from the injured marrow as a second hematopoietic disorder. We have studied a patient with PNH who developed acute myeloblastic leukemia (AML); the blasts from this patient were found to lack DAF as measured by polyclonal antibody binding and fluorescence flow cytometry as well as by immunoblotting. The blasts from 11 other patients with AML bound anti-DAF antibody in amounts similar to normal mononuclear cells from healthy donors. Cells of the human leukemia cell lines HL-60, K562, U937, and HEL also bound anti-DAF antibody. In addition to DAF deficiency, blasts from the PNH patient had undetectable alkaline phosphatase activity, in contrast to human leukemia cell lines. These data suggest that the leukemic cells of the PNH patient arose out of the PNH clone and that AML in the setting of PNH is not a separate disorder.
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PMID:Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone. 243 90

In patients with paroxysmal nocturnal hemoglobinuria (PNH) the RBCs, neutrophils (PMNs), monocytes, and platelets derived from the abnormal clone are deficient in the complement-regulatory protein decay-accelerating factor (DAF). RBC acetylcholinesterase (AChE) and leukocyte alkaline phosphatase (LAP) activities are also characteristically low. DAF, AChE, and LAP are known to be anchored within cell membranes to glycophospholipid-containing phosphatidylinositol (PI). Because PNH progenitors contain DAF that appears to be lost with maturation, it has been proposed that this disorder results from abnormal tethering of these and possibly other proteins to membrane PI. We were puzzled, therefore, that our two PNH patients consistently had normal LAP levels. Consequently, we studied their isolated PMNs to compare DAF and LAP activities in individual cells. PMNs were separated by flow cytometry into DAF-positive and -negative populations by using rabbit anti-DAF antiserum and fluorescein-conjugated goat antirabbit IgG. In both patients the majority of PMNs were DAF deficient, and these cells contained very little alkaline phosphatase activity. In contrast, the smaller, DAF-positive cell populations were phosphatase replete. This is the first demonstration that abnormalities in DAF and LAP activity occur in the same PNH PMN population and strengthens the hypothesis that defective anchoring of proteins to membrane glycophospholipid underlies the pathophysiology of this disorder.
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PMID:The population of paroxysmal nocturnal hemoglobinuria neutrophils deficient in decay-accelerating factor is also deficient in alkaline phosphatase. 245 46

Paroxysmal nocturnal hemoglobinuria (PNH) and the stable phase of chronic myelogenous leukemia (CML) are the two hematological conditions known to be associated with low levels of leukocyte alkaline phosphatase (LAP) activity in peripheral blood polymorphonuclear cells (PMN). LAP mRNA levels were determined in PMN from PNH and CML patients by RNA blotting analysis. In CML, LAP mRNA is undetectable, suggesting either decreased transcription or rapid degradation of the message. Contrarily, in PNH normal or high levels of LAP mRNA are present. This latter finding supports the concept of a deficit in the anchorage of the protein to the plasma membrane through the glycolipid pathway, even though other post-transcriptional mechanisms could be involved.
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PMID:Differences in the expression of alkaline phosphatase mRNA in chronic myelogenous leukemia and paroxysmal nocturnal hemoglobinuria polymorphonuclear leukocytes. 293 Aug 36

Paroxysmal nocturnal hemoglobinuria is characterized by chronic hemolytic anemia, leukopenia, and thrombocytopenia. The increased hemolysis and hemoglobinuria associated with sleep have been observed so frequently that these features have been incorporated into the syndrome's name. Infections, especially of the respiratory and urinary system, can cause hemolytic episodes. Patients with paroxysmal nocturnal hemoglobinuria have increased susceptibility to infections. Some PNH patients are leukopenic, but many are not. It has been reported that leukocyte alkaline phosphatase of granulocytes in patients with PNH is low. As Hartmann and Kohlhouse point out, "The principles of treating infection in PNH seem no different than the therapy of infections in any group. "If major surgery is indicated, preparation should include saline-washed red cells, which would increase the patient's number of circulating normal red blood cells, if necessary. The prognosis is variable. A small percentage of patients with PNH develop leukemia. However, in at least half of all patients, the number of complement sensitive cells decreases, and many of these patients live a fairly normal life.
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PMID:Paroxysmal nocturnal hemoglobinuria: report of case with odontogenic infection. 693 60

The results concerning LPS priming and inactivation are summarized in table 4. This table clearly shows that priming by and inactivation of LPS are mediated via different pathways, because there is no correlation whatsoever between priming and inactivation. LPS priming nicely correlates with CD14 expression. Monocytes express high levels of CD14, and are highly sensitive to LPS. Neutrophils express lower levels of CD14, and also require a higher concentration of LPS to obtain a primed state. Eosinophils express even lower levels of CD14 (if any), and these cells are not primed by LPS up to 150 ng/ml in the presence of serum (data not shown). [table: see text] The inactivation experiments were performed with LPS, but unpublished results from M. Pabst et al. show the same phenomenon with synthetic lipid A. This indicates that the inactivation of LPS is caused by a modification of the lipid A moiety of LPS. As a first step, we tested the hypothesis that the inactivation of LPS is a dephosphorylation of lipid A by alkaline phosphatase (AP). However, AP activity in isolated neutrophils of one of the PNH patients was completely undetectable. Nevertheless, these neutrophils were able to inactivate LPS. This result clearly shows that AP is not the enzyme that inactivates LPS. Secondly, we measured neutral pH 7 phosphatase both in whole cells, and in cell lysate. All cell types tested (neutrophils, eosinophils and monocytes) contained comparable levels of pH 7 phosphatase, but only neutrophils were able to inactivate LPS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphatidyl-inositol-linked CD14 is involved in priming of human neutrophils by lipopolysaccharide (LPS), but not in the inactivation of LPS. 753 Mar 66

Expression of alkaline phosphatase (ALP) on the surface membrane of neutrophils (mNAP) was studied by immunofluorescence using an anti-ALP monoclonal antibody. Fluorescent intensity distribution of mNAP was analyzed using FACS (fluorescence-activated cell sorter). The mean fluorescent intensity (MFI) of the mNAP in this assay was well correlated with the neutrophil ALP (NAP) score demonstrated cytochemically (r = 0.832). mNAP levels in various hematological disorders were evaluated by % mNAP+ cells and MFI. The levels in aplastic anemia and polycythemia vera were significantly higher, and in chronic myelocytic leukemia and paroxysmal nocturnal hemoglobinuria (PNH), the levels were significantly lower compared with the levels in healthy volunteers. Two-color immunofluorescence with anti-ALP and anti-CD16 showed that the PNH clone was essentially negative for mNAP, whereas residual normal neutrophils (CD16+) had levels slightly higher than those in normal individuals. Highly reproducible results were obtained in the blood samples which were stored at 4 degrees C for at least 24 hr without any treatment prior to immunofluorescent staining. No degradation of fluorescent intensity was seen 4 days after staining and fixation. The mNAP assay is simple, without subjective evaluation for quantification, and is useful for differential diagnosis of hematological disorders.
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PMID:Assessment of alkaline phosphatase on the surface membrane of neutrophils by immunofluorescence. 988


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