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:3.5.1.4 (deaminase)
5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sensitivity of human myelogenous leukemia cells to 1-beta-D-arabinofuranosylcytosine (ara-C) during induction of differentiation was examined. Treatment with hemin greatly increased the sensitivity of erythroid leukemia cells to ara-C. The enhancement of ara-C sensitivity by hemin was not as remarkable in nonerythroid leukemia cells. Hemin altered the metabolism of ara-C in human erythroleukemia K562 cells by reducing ara-C deaminase activity, increasing intracellular accumulation of ara-C, and activating the nucleoside kinases. These alterations may be involved in the enhancing effect of hemin on sensitivity of ara-C. These results suggest that some inducers of differentiation potentiate the antileukemic effect of ara-C on human erythroleukemia cells.
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PMID:Hemin enhances the sensitivity of erythroleukemia cells to 1-beta-D-arabinofuranosylcytosine by both activation of deoxycytidine kinase and reduction of cytidine deaminase activity. 187 97

Murine erythroleukaemia (MEL) cells are virus-transformed erythroid precursor cells that, when induced to differentiate by dimethyl sulphoxide (DMSO), will initiate haem biosynthesis by the induction and synthesis de novo of all of the enzymes of the haem-biosynthetic pathway. The activities of porphobilinogen (PBG) deaminase (EC 4.3.1.8), coproporphyrinogen oxidase (EC 1.3.3.3), protoporphyrinogen oxidase (EC 1.3.3.4), ferrochelatase (EC 4.99.1.1) and NADH:ferric iron reductase, as well as the synthesis of the enzyme ferrochelatase and the levels of excreted porphyrins, were monitored during DMSO-induced differentiation of MEL cells in culture. The data demonstrate that PBG deaminase and protoporphyrinogen oxidase activities rise rapidly and early, in comparison with ferrochelatase activity, which rises more slowly, and coproporphyrinogen oxidase activity, which decreases by 60% within 24 h of induction before returning to initial levels by 72 h. NADH:ferric iron reductase activity increases slightly, but is always present at levels higher than needed for haem synthesis. Total immunoprecipitable ferrochelatase also rises slowly and parallels the increase in its activity, suggesting that it is not synthesized early in a slowly processed precursor form. Examination of culture media demonstrated that, whereas excretion of protoporphyrin and coproporphyrin occurs within 24 h of induction, coproporphyrin is excreted in amounts 4-15 times greater than protoporphyrin.
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PMID:Multiple mechanisms for the regulation of haem synthesis during erythroid cell differentiation. Possible role for coproporphyrinogen oxidase. 202 19

Erythropoietin (Epo) was found to act as a concentration-dependent inducer of aminolevulinic acid (ALA) synthase and porphobilinogen (PBG) deaminase in normal human bone marrow in culture. Epo increased enzymatic activities in individual plated nucleated cells. At a low concentration of Epo, heme oxygenase activity did not change in human bone marrow erythroid progenitor cells. However, Epo at a concentration of 2 U/ml increased heme oxygenase as demonstrated by an increase in both the enzyme protein and its mRNA. In experiments with an inhibitor of heme synthesis, succinylacetone (SA), Epo failed to stimulate erythroid colony-forming unit (CFU-E) growth, but this CFU-E inhibition by SA was completely overcome by the addition of hemin. Epo nevertheless potentiated induction of ALA synthase in the presence of SA. Hemin exerted its regulatory role by negative feedback on ALA synthase in the presence of SA and Epo. Heme potentiated Epo action and resulted in the increase of human marrow erythroid progenitor cell proliferation and differentiation and a concomitant stimulation of ALA synthase and PBG deaminase. The potentiating effects of hemin on CFU-E growth were observed in human bone marrow cells cultured in media supplemented with fetal calf serum or serum-free media with interleukin 3 (IL-3). These results indicate that Epo is a potent inducer of ALA synthase and PBG deaminase in normal human bone marrow. In addition, our results may explain the mechanisms by which heme potentiates Epo or IL-3 enhancement of erythropoiesis. 1) Heme may stimulate the translation of several globin and nonglobin mRNAs, including those of ALA synthase and PBG deaminase; 2) as endogenous cellular heme synthesis reaches optimal levels, heme exerts its regulatory role on ALA synthase by negative feedback inhibition. Additionally, an increase in cellular heme may lead to an increase in its own degradation by induction of heme oxygenase.
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PMID:Erythropoietin controls heme metabolic enzymes in normal human bone marrow culture. 276 84

A common two-allele MspI restriction fragment length polymorphism of the human erythroid porphobilinogen (PBG)-deaminase gene was investigated in 33 unrelated patients with acute intermittent porphyria (AIP) and 20 controls. The polymorphism was tightly linked (lod score 3.14; no recombinants) to the locus for AIP as identified by measurement of erythrocyte PBG-deaminase activity. The frequency of the polymorphism in the AIP patients did not differ significantly from that in the controls. No common polymorphisms for eight other restriction endonucleases were found in either group. In 30 of the AIP patients no crossreacting immunological material (CRIM) was produced by the mutant PBG-deaminase allele. The MspI polymorphism enabled each PBG-deaminase allele to be distinguished in subjects heterozygous for the polymorphism; thus a major gene deletion was excluded as the cause of the CRIM-negative mutation in all of the 18 families that contained an affected CRIM-negative individual heterozygous for the polymorphism. In suitable families, the MspI polymorphism provides a more certain way of identifying carriers of the AIP gene than current enzymatic methods and major gene deletions are unlikely to be present in more than a small proportion of the commonest type of AIP, the CRIM-negative form.
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PMID:DNA polymorphism of human porphobilinogen deaminase gene in acute intermittent porphyria. 288 41

The overall aim of our group's work is to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. We have been successful in cloning two non-globin genes of interest: the first encodes the rabbit red cell-specific lipoxygenase (LOX), which has a role in degrading mitochondrial lipids during maturation of the reticulocyte to the erythrocyte; and the second, mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterization of the GSHPX gene revealed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding the role of mRNA sequence context effects in codon recognition. In contrast with the beta-globin locus, very little is known about the mechanisms responsible for the erythroid-specific expression of the alpha-globin genes. By a combination of functional transfection assays and studies of the interactions of nuclear sequence-specific DNA-binding proteins with promoter sequences in vitro, we have recently defined two regions upstream of the mouse alpha-globin gene involved in its erythroid-specific expression: one contains a sequence motif (GATAAG) that binds to a species-conserved and erythroid-specific factor both in vitro and in vivo. Interestingly, GATAAG motifs binding the same factor are found also in the mouse and chicken adult beta-globin gene promoters, the erythroid-specific promoter of the haem pathway enzyme, porphobilinogen (PBG) deaminase and the chicken beta-globin 3' enhancer. We are now commencing purification of this erythroid-specific GATAAG-binding factor, investigating in more detail how it functions in relation to other globin gene control regions and determining whether GATAAG-like regions have a functional role in the erythroid-specific expression of other genes. We have begun to investigate the regulation of the GSHPX and red cell LOX genes. The presence of tissue-specific 3' DNAse I-hypersensitive sites (DHSS) suggests that different 3' flanking regions of the GSHPX gene may be important in its regulation in the various cell types in which it is highly expressed, i.e. erythroid cells, liver and kidney.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:cis and trans control of erythroid cell-specific gene expression during erythropoiesis. 315 55

In this study, we demonstrated that benzene and its metabolites, phenol and hydroquinone, were toxic to human burst-forming unit-erythroid (BFU-E) growth, hydroquinone being the most toxic. Phenol (10(-4) M) was also found to have a marked toxicity on stromal cell colony formation. BFU-E binding with human-tumor necrosis factor (rHu-TNF) was linear with the number of BFU-E colonies. Recombinant rHu-TNF suppressed BFU-E growth in a dose-dependent manner and this was reversed with anti-TNF antibody. Binding studies of rHu-TNF for human K562 cells indicated that K562 cells have a binding constant of approximately 1075 per cell. The heme pathway enzymes, uroporphyrinogen deaminase, and heme oxygenase activities were measured in BFU-E cultures exposed to iron, interleukins (1 and 2), and various lymphocyte and macrophage-conditioned media with or without hemin. In most instances, hemin was found to stimulate the heme synthetic pathway in the presence of these agents. Iron and adherent (macrophage) cell conditioned media (CM) were found to stimulate heme oxygenase activity. Macrophage CM was found to suppress erythropoiesis in contrast to phytohemagglutinin-stimulated leukocyte (PHAL)-CM, which enhanced erythroid growth. In addition, porphobilinogen deaminase levels were greater in 14-day cultures containing hemin plus PHAL-CM as compared with hemin alone. These results are discussed with respect to the generation of hematopoietic inhibitory-stimulatory factors by the marrow microenvironment and their effects on heme synthesis and degradation.
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PMID:Microenvironmental cytokines and expression of erythroid heme metabolic enzymes. 331 Dec 13

During dimethyl sulfoxide (DMSO)-stimulated differentiation of murine erythroleukemia (MEL) cells, one of the early events is the induction of the heme biosynthetic pathway. While recent reports have clearly demonstrated that GATA-1 is involved in the induction of erythroid cell-specific forms of 5-aminolevulinate synthase (ALAS-2) and porphobilinogen (PBG) deaminase and that cellular iron status plays a regulatory role for ALAS-2, little is known about regulation of the remainder of the pathway. In the current study, we have made use of a stable MEL cell mutant (MEAN-1) in which ALAS-2 enzyme activity is not induced by DMSO, hexamethylene bisacetamide (HMBA), or butyric acid. In this cell line, addition of 2% DMSO to growing cultures results in the normal induction of PBG deaminase and coproporphyrinogen oxidase but not in the induction of the terminal two enzymes, protoporphyrinogen oxidase and ferrochelatase. These DMSO-treated cells did not produce mRNA for beta-globin and do not terminally differentiate. In addition, the cellular level of ALAS activity declines rapidly after addition of DMSO, indicating that ALAS-1 must turn over rapidly at this time. Addition of 75 microM hemin alone to the cultures did not induce cells to terminally differentiate or induce any of the pathway enzymes. However, the simultaneous addition of 2% DMSO and 75 microM hemin caused the cells to carry out a normal program of terminal erythroid differentiation, including the induction of ferrochelatase and beta-globin. These data suggest that induction of the entire heme biosynthetic pathway is biphasic in nature and that induction of the terminal enzymes may be mediated by the end product of the pathway, heme. We have introduced mouse ALAS-2 cDNA into the ALAS-2 mutant cell line (MEAN-1) under the control of the mouse metallothionein promoter (MEAN-RA). When Cd and Zn are added to cultures of MEAN-RA in the absence of DMSO, ALAS-2 is induced but erythroid differentiation does not occur and cells continue to grow normally. In the presence of metallothionein inducers and DMSO, the MEAN-RA cells induce in a fashion similar to that found with the wild-type 270 MEL cells. Induction of the activities of ALAS, PBG deaminase, coproporphyrinogen oxidase, and ferrochelatase occurs. In cultures of MEAN-RA where ALAS-2 had been induced with Cd plus Zn 24 h prior to DMSO addition, onset of heme synthesis occurs more rapidly than when DMSO and Cd plus Zn are added simultaneously. This study reveals that induction of ALAS-2 alone is not sufficient to induce terminal differentiation of the MEAN-RA cells, and it does not appear that ALAS-2 alone is the rate-limiting enzyme of the heme biosynthetic pathway during MEL cell differentiation.
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PMID:Biphasic ordered induction of heme synthesis in differentiating murine erythroleukemia cells: role of erythroid 5-aminolevulinate synthase. 841 1

Acute intermittent porphyria (AIP) is the most frequent acute porphyria. Symptomatic patients and asymptomatic gene carriers are characterized by a reduction of their porphobilinogen-deaminase (PBG-D) activity to 50%, which is sufficient for porphyrin biosynthesis. PBG-D is encoded by two different mRNAs which are expressed in a tissue-specific manner. In classical AIP, the enzyme activity is reduced in erythroblasts and all other heme-forming body cells, whereas in the variant form of AIP, the PBG-D activity in erythroid tissues remains normal. Acute porphyria attacks can occur in gene carriers when the biosynthesis of heme is increased by drugs, low calorie intake, alcohol consumption or infections. Under these conditions, PBG-D cannot convert the precursors adequately so that PBG and delta-aminolevulinate accumulate. This may lead to neurovisceral symptoms and other neurological complications which are potentially life threatening. In patients with AIP, mutation analysis by PCR-DGGE (denaturing gradient gel electrophoresis) is becoming increasingly important since it also permits rapid identification of their presymptomatic relatives. Using this technique, more than 120 mutations have been identified in the PBG-D gene. When identified, the family members are informed about their genetic predisposition and are taught how to prevent porphyric attacks. Here, I illustrate this preventive strategy by describing a German kindred of an affected patient with the variant form of AIP with 17 family members.
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PMID:Acute intermittent porphyria: mutation analysis and identification of gene carriers in a German kindred by PCR-DGGE analysis. 1034 7

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