Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three Beagles with chronic anemia and reticulocytosis were studied. The dogs originated from a large breeding colony and appeared clinically normal with the exception of splenomegaly. The PCV ranged from 30 to 39% (normal, 46 to 56%), with reticulocyte indices of 2.3 to 9.9. Red blood cells were morphologically normal, and examination of marrow aspirates revealed erythroid hyperplasia. Shortened chromium-51 RBC life-spans (7.2 to 15.4 days in anemic dogs; 22.2 to 25.2 days in control dogs) documented a hemolytic anemia. Acquired causes of hemolytic anemia were ruled out. Red blood cells had normal glycolytic enzyme activities, no evidence of unstable or abnormal hemoglobin, and had altered osmotic fragility curves. The breeding of 2 anemic dogs resulted in offspring with anemia and reticulocytosis. Polyacrylamide gel electrophoresis revealed no abnormalities in RBC membrane cytoskeletal proteins in all anemic adult dogs and in 3 offspring.
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PMID:Hereditary nonspherocytic hemolytic anemia in beagles. 245 89

Two children with nonspherocytic anaemia and pyruvate kinase deficiency had their diagnosis delayed due to normal initial estimations of enzyme activity. Repeated analyses involving other glycolytic enzymes documented an increased glucose-6-phosphate dehydrogenase activity as a function of high reticulocyte counts. The pyruvate kinase activity showed subnormal values. By simple comparison of both enzyme activities a true pyruvate kinase activity of below 50% was estimated thus rendering the diagnosis of pyruvate kinase deficiency highly probable. Analyses of more than one glycolytic enzyme should be performed in young children with otherwise unexplained haemolysis and associated high reticulocyte counts.
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PMID:[Diagnosis of pyruvate kinase deficiency]. 765 57

Prolonged haemolysis may accompany infection with Plasmodium falciparum. We observed prolonged haemolysis in 4 of 10 patients with this type of malaria after parasitological cure. IgM antibodies specific for the glycolytic enzyme triosephosphate isomerase were detected in these patients' sera. Clinical recovery and a decrease in haemolysis coincided with a fall in these autoantibodies. In vitro, affinity purified autoantibodies isolated from the sera directed against triosephosphate isomerase induced lysis of erythrocytes and activation of complement as shown by the 51Cr release assay. We assume that autoantibodies against triosephosphate isomerase contribute to the development of prolonged haemolysis and anaemia in P falciparum malaria.
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PMID:Prolonged haemolytic anaemia in malaria and autoantibodies against triosephosphate isomerase. 790 38

Two billion years of aerobic evolution have resulted in mammalian cells and tissues that are extremely oxygen-dependent. Exposure to oxygen tensions outside the relatively narrow physiological range results in cellular stress and toxicity. Consequently, hypoxia features prominently in many human diseases, particularly those associated with blood and vascular disorders, including all forms of anemia and ischemia. Bioenergetic enzymes have evolved both acute and chronic oxygen sensing mechanisms to buffer changes of oxygen tension; at normal P(O) oxidative phosphorylation is the principal energy supply for eukaryotic cells, but when the P(O) falls below a critical mark metabolic switches turn off mitochondrial electron transport and activate anaerobic glycolysis. Without this switch cells would suffer an immediate energy deficit and death at low P(O). An intriguing feature of the switching is that the same conditions that regulate energy metabolism also regulate bioenergetic genes, so that enzyme activity and transcription are regulated simultaneously, albeit with different time courses and signaling pathways. In this review we explore the pathways mediating hypoxia-regulated glycolytic enzyme gene expression, focusing on their atavistic traits and evolution.
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PMID:Evolution of the coordinate regulation of glycolytic enzyme genes by hypoxia. 1287 60

Erythrocyte pyruvate kinase (PK) is an important glycolytic enzyme, and manipulation of its regulatory behavior by allosteric modifiers is of interest for medicinal purposes. Human-erythrocyte PK was expressed in Rosetta cells and purified on an Ni-NTA column. A search of the small-molecules database of the National Cancer Institute (NCI), using the UNITY software, led to the identification of several compounds with similar pharmacophores as fructose-1,6-bisphosphate (FBP), the natural allosteric activator of the human kinases. The compounds were subsequently docked into the FBP binding site using the programs FlexX and GOLD, and their interactions with the protein were analyzed with the energy-scoring function of HINT. Seven promising candidates, compounds 1-7, were obtained from the NCI, and subjected to kinetics analysis, which revealed both activators and inhibitors of the R-isozyme of PK (R-PK). The allosteric effectors discovered in this study could prove to be lead compounds for developing medications for the treatment of hemolytic anemia, sickle-cell anemia, hypoxia-related diseases, and other disorders arising from erythrocyte PK malfunction.
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PMID:Identification of novel allosteric regulators of human-erythrocyte pyruvate kinase. 1802 74

Erythropoietin (EPO) has been used to correct cancer-related anemia and to improve tumor hypoxia, which both adversely affect the clinical condition of cancer patients and response to radiotherapy. Data available on the effects of EPO treatment in cancer are, however, conflicting. Several clinical studies investigating the influence of EPO treatment have given contradictory results as to whether or not this treatment positively influences survival. In light of these conflicting results, we studied the effects of EPO treatment either alone or in combination with radiotherapy on tumor oxygenation and on the expression pattern of several proteins related to tumor metabolism, survival, and spread in a rat colorectal cancer model. We found a statistically significant upregulation of hexokinase I, N-cadherin, and glucose transporter 3 when EPO treatment was combined with radiotherapy. Because these three proteins have distinct functions in protecting the cell in compromised conditions, these results indicate a detrimental role for the combination of EPO treatment and radiotherapy through the stimulation of tumor-cell metabolism, inhibition of apoptosis, and stimulation of tumor spread and seem to indicate that recombinant human EPO treatment negatively modulates radiotherapy efficacy.
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PMID:Combined effect of EPO and radiotherapy on the expression of endogenous molecular markers of tumor metabolism and metastasis. 1987 86

Glycerolipids are structural components for membranes and serve in energy storage. We describe here the use of a photodynamic selection technique to generate a population of Chinese hamster ovary cells that display a global deficiency in glycerolipid biosynthesis. One isolate from this population, GroD1, displayed a profound reduction in the synthesis of phosphatidylcholine, phosphatidylethanolamine, and triglycerides but presented high levels of phosphatidic acid and normal levels of phosphatidylinositol synthesis. This was accompanied by a reduction in phosphatidate phosphatase 1 (PAP1) activity. Expression cloning and sequencing of the cDNA obtained from GroD1 revealed a point mutation, Gly-189 --> Glu, in glucose-6-phosphate isomerase (GPI), a glycolytic enzyme involved in an inherited disorder that results in anemia and neuromuscular symptoms in humans. GPI activity was reduced by 87% in GroD1. No significant differences were found in DNA synthesis, protein synthesis, and ATP levels, whereas glycerol 3-phosphate levels were increased in the mutant. Expression of wild-type hamster GPI restored GPI activity, glycerolipid biosynthesis, and PAP1 activity in GroD1. Two additional, independently isolated GPI-deficient mutants displayed similar phenotypes with respect to PAP1 activity and glycerolipid biosynthesis. These findings uncover a novel relationship between GPI, involved in carbohydrate metabolism, and PAP1, a lipogenic enzyme. These results may also help to explain neuromuscular symptoms associated with inherited GPI deficiency.
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PMID:Isolation of novel animal cell lines defective in glycerolipid biosynthesis reveals mutations in glucose-6-phosphate isomerase. 1990 19

Identification of allosteric binding site modulators have gained increased attention lately for their potential to be developed as selective agents with a novel chemotype and targeting perhaps a new and unique binding site with probable fewer side effects. Erythrocyte pyruvate kinase (R-PK) is an important glycolytic enzyme that can be pharmacologically modulated through its allosteric effectors for the treatment of hemolytic anemia, sickle-cell anemia, hypoxia-related diseases, and other disorders arising from erythrocyte PK malfunction. An in-silico screening approach was applied to identify novel allosteric modulators of pyruvate kinase. A small-molecules database of the National Cancer Institute (NCI), was virtually screened based on structure/ligand-based pharmacophore. The virtual screening campaign led to the identification of several compounds with similar pharmacophoric features as fructose-1,6-bisphosphate (FBP), the natural allosteric activator of the kinase. The compounds were subsequently docked into the FBP-binding site using the programs FlexX and GOLD, and their interactions with the protein were analyzed with the energy-scoring function of HINT. Seven promising candidates were obtained from the NCI and subjected to kinetics analysis, which revealed both activators and inhibitors of the R-isozyme of PK (R-PK).
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PMID:In silico-screening approaches for lead generation: identification of novel allosteric modulators of human-erythrocyte pyruvate kinase. 2205

Novel therapies in development have brought a new focus on pyruvate kinase deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy. Decisions to transfuse and/or splenectomise must be individualised. Haematopoietic stem cell transplant has been pursued in a small number of patients with mixed outcomes. Novel treatment approaches, which range from a small molecule pyruvate kinase activator to gene therapy, may transform the way in which PKD is managed in the future. In this review, we discuss the pathophysiology of PKD and present our approaches to diagnosis, monitoring and management of patients with this anaemia.
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PMID:How we manage patients with pyruvate kinase deficiency. 3105 20

Phosphoglycerate kinase (PGK) is glycolytic enzyme critical in the creation of adenosine triphosphate. Mutations in the gene for this enzyme, PGK1, are associated with PGK deficiency, which is characterized by neurologic symptoms, nonhereditary spherocytic hemolytic anemia, and myopathy. We present a 20-year-old male with a novel c.461T>C (p.L154P) PGK1 mutation and clinical disease complicated by anemia and neurological symptoms. There is no recommended treatment for PGK deficiency. Because of our patient's advanced disease progression, we initiated serial blood transfusions and report significant subjective improvement in the patient's physical condition before his passing from PGK deficiency-related complications.
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PMID:Therapeutic Benefit of Blood Transfusion in a Patient With Novel PGK1 Mutation (c.461T>C [p.L154P]). 3095 Oct 21


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