Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceruloplasmin (Cp) is an abundant, copper-containing plasma protein with an important role in iron homeostasis. Patients with hereditary Cp deficiency have iron deposits in liver and other organs, consistent with impaired iron flux. The mild anemia reported in some patients suggests a possible role for Cp in iron delivery to red cell precursors during erythropoiesis. To investigate this function of Cp, we determined the hematologic parameters in Cp-deficient mice under normal conditions and after erythropoiesis-inducing stress. Cp(-/-) mice have below normal hematocrit, red cell hemoglobin and volume, and serum iron. Red cell number and turnover and reticulocyte counts were identical in Cp(-/-) and Cp(+/+) mice. Thus, Cp(-/-) have mild microcytic, hypochromic anemia consistent with normal red cell formation but defective iron availability. Cp(-/-) and Cp(+/+) mice subjected to phenylhydrazine-induced hemolytic anemia exhibited identical decreases in hematologic parameters, but Cp(-/-) mice showed diminished recovery after removal of the stress. Administration of purified human Cp or iron-saturated transferrin to Cp(-/-) mice partially restored hemoglobin formation in reticulocytes. The mild anemia in Cp(-/-) mice and the diminished response to stress may reflect inefficient recycling of iron between the reticuloendothelial and erythropoietic systems. Our findings suggest a role for Cp in erythropoiesis by providing sufficient iron to the erythroid tissue and that the requirement for Cp is raised after erythropoietic stress.
Blood Cells Mol Dis
PMID:Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice. 1552 56

A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.
Mol Genet Metab 2004 Nov
PMID:Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. 1554 92

Human erythrocyte pyrimidine 5'-nucleotidase, PN-I, catalyzes the dephosphorylation of pyrimidine nucleoside monophosphates. The enzyme also possesses phosphotransferase activity, transferring phosphate groups between pyrimidine nucleoside monophosphates and various pyrimidine nucleosides. Deficiency of the enzyme activity is associated with a hemolytic anemia. PN-I cDNA has been expressed in Escherichia coli, yielding a fully active recombinant enzyme, which was purified to homogeneity and extensively characterized. Multiple sequence alignment of PN-I and homologues proteins revealed the existence of conserved regions, whose importance in catalysis was examined by performing experiments designed to intercept covalent intermediates as strongly suggested by our previous kinetic studies. Furthermore, a functional analysis of the enzyme was carried out through site-directed mutagenesis designed on the basis of the sequence of the identified conserved regions as well as mutations observed in PN-I-deficient patients.
Cell Mol Life Sci 2005 Jul
PMID:Evidence for essential catalytic determinants for human erythrocyte pyrimidine 5'-nucleotidase. 1596 58

Hemoglobin (Hb) C (alpha2beta(2)6Glu-Lys) is a variant Hb found mainly in West Africa where individuals carrying both Hb C and Hb S (alpha2beta(2)6Glu-Val) usually have a disease similar to sickle cell disease. The Hb C molecule has reduced solubility leading to crystal formation and hemolytic anemia. We report a hitherto undescribed interaction of Hb C and Hb Malay (alpha2beta(2)19Asn-Ser) in a Thai individual. She was a 24-year-old pregnant woman with moderate anemia who had the following hematologic data; Hb 8.9 g/dl, Hct 30.0%, MCV 81.0 fl, MCH 24.1 pg, MCHC 29.7 g/dl, RDW 17.1% and instead of Hb crystal a marked number of target cell in peripheral blood was observed. Hb analysis revealed 22.5% Hb Malay, 64.6% Hb C and 4.5% Hb A2. Globin gene analyses demonstrated that she carried the betaC mutation (beta6: GAG-AAG) in trans to the betaMalay mutation (beta19: AAC-AGC). Hematologic data of the patient were compared to those of the compound heterozygote for Hb C and Hb E (alpha2beta(2)26Glu-Lys) found in 5 other unrelated Thai pregnant women and 11 pregnant women with Hb C heterozygote with or without co-inheritance of alpha-thalassemia who had much lower Hb C levels and the non-pregnant women with Hb C heterozygote and a compound Hb E/Hb Malay syndrome. Different genotype-phenotype correlations observed in these Thai patients with Hb C disorders are illustrated.
Blood Cells Mol Dis
PMID:Compound heterozygote states for Hb C/Hb Malay and Hb C/Hb E in pregnancy: a molecular and hematological analysis. 1598 9

Glutathione (GSH), one of the most important antioxidants in the eukaryotic organism, is synthesized in a two-step procedure where the last step is catalysed by the enzyme glutathione synthetase (GSS). GSS deficiency is inherited autosomal recessively, and patients with this disease can be divided into three groups, according to their clinical phenotype. Mildly affected patients have mutations affecting the stability of the enzyme, causing a compensated haemolytic anaemia; moderately affected patients have, in addition, metabolic acidosis; and severely affected patients also develop neurological defects and show increased susceptibility to bacterial infections. Moderately and severely affected patients have mutations that compromise the catalytic properties of the enzyme. 5-Oxoprolinuria appears in all three groups, but is more pronounced in the two latter groups. Today, no cure can be offered these patients; they are given vitamins C and E to boost their antioxidant levels, and bicarbonate to correct metabolic acidosis.
Cell Mol Life Sci 2005 Sep
PMID:Glutathione synthetase deficiency. 1599 Sep 54

Earlier we have reported two G6PD variants viz.; G6PD Jamnagar and G6PD Rohini. The enzymes from both the variants showed altered biochemical properties with mild enzyme deficiency and were classified as unique Class III variants. G6PD Jamnagar was found to be associated with drug-induced hemolytic anemia whereas G6PD Rohini was picked up during a population survey. Subsequent molecular studies on the DNA from both the cases showed the presence of the Kerala-Kalyan (949 G-->A) mutation. Hence, this study besides supporting the fact that biochemically distinct variants could have the same mutation at the molecular level also highlights the importance of molecular characterization of G6PD variants.
Blood Cells Mol Dis
PMID:Two distinct Indian G6PD variants G6PD Jamnagar and G6PD Rohini caused by the same 949 G-->A mutation. 1599 81

Oxidant and free radical-generating system were used to promote oxidative damage in erythrocytes. Among the oxidants used, phenylhydrazine represents one of the most investigated intracellular free radical-generating probes, which in the presence of haemoglobin auto-oxidises and give rise to hydroxyl radical, a marker for cellular damage. Erythrocyte, as a single cell, is a good model to be used for studying the haemolytic mechanism of anaemia. Our present investigations reveal increased lipid peroxidation of erythrocyte using phenylhydrazine as well as other oxygen-generating systems (hydrogen peroxide, iron with hydrogen peroxide). It has further been observed that not only lipid peroxidation, phenylhydrazine causes significant elevation in methemoglobin formation, catalase activity and turbidity, in the above system, which are the typical characteristics of haemolytic anaemia. However, exogenous administration of green tea leaf extract and ascorbic acid as natural antioxidants and free radical scavengers were shown to protect separately increased lipid peroxidation caused by phenylhydrazine, though the degree of protection is more in case of green tea leaf extract than ascorbic acid. Results suggest that oxidative damage in vivo due to haemolytic disease may be checked to some extent by using natural antioxidants.
Mol Cell Biochem 2005 Aug
PMID:Oxidant induced injury of erythrocyte-role of green tea leaf and ascorbic acid. 1613 2

Iron-derived reactive oxygen species are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic hemolytic anemia, vasculitis, and reperfusion injury. One abundant source of redox active iron is heme, which is inherently dangerous when released from intracellular heme proteins. The present review concerns the involvement of heme in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelium to heme greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of reactive oxygen. Free heme also promotes the conversion of low-density lipoprotein (LDL) into cytotoxic oxidized products. Only because of its abundance, hemoglobin probably represents the most important potential source of heme within the vascular endothelium; hemoglobin in plasma, when oxidized, transfers heme to endothelium and LDL, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defense against such toxicity, upon exposure to heme or hemoglobin, endothelial cells up-regulate heme oxygenase-1 and ferritin. Heme oxygenase-1 is a heme-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide, and the most dangerous product - free redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. Ferritin serves as a protective gene by virtue of antioxidant, antiapoptotic, and antiproliferative actions. These homeostatic adjustments have been shown effective in the protection of endothelium against the damaging effects of exogenous heme and oxidants. The central importance of this protective system was recently highlighted by a child diagnosed with heme oxygenase-1 deficiency, who exhibited extensive endothelial damage.
Mol Nutr Food Res 2005 Nov
PMID:Heme, heme oxygenase and ferritin in vascular endothelial cell injury. 1620 35

Membrane-bound proteases are involved in various regulatory functions. Our previous study indicated that the N-terminal region of an open reading frame, PH1510 (residues 16-236, designated as 1510-N) from the hyperthermophilic archaeon Pyrococcus horikoshii, is a serine protease with a catalytic Ser-Lys dyad that specifically cleaves the C-terminal hydrophobic residues of a membrane protein, the stomatin-homolog PH1511. In humans, an absence of stomatin is associated with a form of hemolytic anemia known as hereditary stomatocytosis, but the function of stomatin is not fully understood. Here, we report the crystal structure of 1510-N in dimeric form. Each active site of 1510-N is rich in hydrophobic residues, which accounts for the substrate-specificity. The monomer of 1510-N shows structural similarity to one monomer of Escherichia coli ClpP, an ATP-dependent tetradecameric protease. But, their oligomeric forms are different. Major contributors to dimeric interaction in 1510-N are the alpha7 helix and beta9 strand, both of which are missing from ClpP. While the long handle region of ClpP contributes to the stacking of two heptameric rings, the corresponding L2 loop of 1510-N is disordered because the region has little interaction with other residues of the same molecule. The catalytic Ser97 of 1510-N is in almost the same location as the catalytic Ser97 of E.coli ClpP, whereas another residue, Lys138, presumably forming the catalytic dyad, is located in the disordered L2 region of 1510-N. These findings suggest that the binding of the substrate to the catalytic site of 1510-N induces conformational changes in a region that includes loop L2 so that Lys138 approaches the catalytic Ser97.
J Mol Biol 2006 May 12
PMID:Molecular structure of a novel membrane protease specific for a stomatin homolog from the hyperthermophilic archaeon Pyrococcus horikoshii. 1657 50

Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and acute renal failure. Lack of complement inactivating factor H predisposes to the development of atypical HUS. Little is known about mechanisms linking complement activation with loss of erythrocyte integrity during HUS. Recent studies disclosed that increased cytosolic Ca2+ activity and cellular ceramide trigger programmed erythrocyte death or eryptosis, characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. In the present study, we investigated whether eryptosis occurs during the course of HUS. To this end, erythrocytes from healthy volunteers were exposed to plasma from a patient with severe idiopathic recurrent HUS secondary to factor H depletion. Phosphatidylserine exposure (Annexin binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence), and ceramide formation [anti-ceramide antibody and enzymatic (diacylgycerol kinase) analysis] were determined. Exposure of erythrocytes to plasma from the patient, but not to plasma from healthy individuals, triggered Annexin binding. The effect of plasma on erythrocyte Annexin binding was abolished by plasmapheresis or filtration at 30 kDa. It was paralleled by formation of ceramide and increase of cytosolic Ca2+ activity. Enhanced Annexin binding of erythrocytes from healthy individuals was observed after exposure to plasma from three other patients with HUS. The proeryptotic effect of patient plasma was mimicked by exposure to the Ca2+ ionophore ionomycin, and eryptosis was potentiated in the presence of cell membrane-permeable C6-ceramide. Furthermore, in vitro complement activation similarly triggered erythrocyte phosphatidylserine exposure, an effect which was blunted by the addition of factor H. In conclusion, our present observations disclose a novel, pathophysiological, factor-H dependent mechanism leading to injury of erythrocytes during the course of hemolytic uremic syndrome.
J Mol Med (Berl) 2006 May
PMID:Suicidal death of erythrocytes in recurrent hemolytic uremic syndrome. 1664 57


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