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)

Numerous porphyrin auxotrophic mutants have been isolated from the 168 trpC2 strain of Bacillus subtilis by selection with streptomycin. Some of them could be supplemented with ALA while the majority grew only in the presence of haemin. Among the latter strains, the syntropism test allowed to distinguish two groups different in phenotype, viz., feeders accumulating ALA and non-feeders accumulating instead of ALA other porphyrin intermediates. On the basis of transductional studies, feeders and non-feeders could be divided into two and four groups, respectively. Biochemical investigation revealed that, with one exception, one enzyme of the porphyrin biosynthesis was coordinated to each hem locus. The following genes were identified:hemB yields ALA-dehydrase;hemC yields PBG-deaminase; hemE yields uroporphyrinogen decarboxylases; hemF yields coproporphyrinogen oxidase; hemG yields protoporphyrin-iron-chelatase.
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PMID:Genetic and biochemical analysis of haemin dependent mutants of Bacillus subtilis. 80 3

Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a partial deficiency of porphobilinogen (PBG) deaminase. Different subtypes of the disease have been defined, and more than 10 different mutations have been described. We focused our study on exon 10, since we previously found that three different mutations were located in this exon and that two of them seemed to be relatively common. We used denaturing gradient gel electrophoresis (DGGE) after in vitro amplification to detect all possible mutations in exon 10 in 41 unrelated AIP patients. In about one-fourth of these patients we could distinguish three abnormal migration patterns, indicating the presence of various mutations. Additional sequencing demonstrated the presence of three different single-base substitutions. Two of these mutations had already been described. A third one consisted of a C-to-T transition located at position 499 of the PBG deaminase mRNA and resulted in an Arg-to-Trp substitution. All three mutations were found in patients with cross-reacting immunological material (CRIM)-positive forms of AIP. The high frequency of these mutations make DGGE analysis of exon 10 a useful approach allowing the direct direction of the DNA abnormality in most of the families with the CRIM-positive subtype of AIP.
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PMID:High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria. 149 94

A sister and brother with severe porphobilinogen (PBG) deaminase deficiency are described. Each of their parents carries a different mutation for acute intermittent porphyria and the children are homozygous for the PBG-deaminase deficiency that causes this disorder. Both are compound heterozygotes for adjacent base transitions in the same codon in exon 10 of the PBG deaminase gene.
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PMID:Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene. 157 72

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder affecting the enzyme porphobilinogen (PBG) deaminase in the heme biosynthetic pathway. The highest prevalence of the disorder has been observed in Scandinavia, especially in northern Sweden (Lappland) where it occurs with a prevalence of 1 in 1500. Biochemical assays of the activity and concentration of PBG deaminase in red blood cells, haplotyping with 4 intragenic restriction fragment length polymorphisms (RFLPs) (MspI, PstI, BstNI, ApaLI) using the polymerase chain reaction (PCR) and screening for known base substitutions by oligonucleotide probes was performed in 28 Swedish AIP families. There was no close relationship between haplotype, biochemical findings (PBG deaminase activity, enzyme-linked immunosorbent assay [ELISA], and excess urinary excretion of delta-aminolevulinic acid or PBG), and a specific mutation. Three different haplotypes were identified. The haplotype 2/1/1/2 (MspI/PstI/BstNI/ApaLI; +/-/-/+) was found to be the most frequent among gene carriers (P less than 0.001). The disease segregated with the haplotype 2/1/1/2 in the 10 families originating from northern Sweden. All 28 families were screened for three known point mutations. Only one was found to carry one of these mutations. Thus, the genetic background of AIP is heterogeneous in Sweden.
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PMID:Genetic heterogeneity of the porphobilinogen deaminase gene in Swedish families with acute intermittent porphyria. 167 34

Activities of delta-aminolevulinic acid (ALA) dehydratase and porphobilinogen (PBG) deaminase, and haem content were determined in EB-virus transformed lymphocytes from two patients with homozygous ALA dehydratase deficiency, and their family members to determine the expression of the specific gene defect in this cell type. ALA dehydratase activity, but not PBG deaminase activity or haem content, was markedly decreased in lymphocyte preparations from both patients with homozygous enzyme deficiency, and moderately decreased in subjects heterozygous for enzyme deficiency. Immunochemical quantitation of erythrocyte ALA dehydratase suggested the presence of a cross-reactive material in a patient with a late-onset of acute hepatic porphyria due to the homozygous enzyme deficiency.
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PMID:Hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes and erythrocytes. 190 39

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

We studied the porphyrin metabolism of a 7-year-old Japanese boy with erythropoietic protoporphyria (EPP) and his family members. Leukocyte ferrochelatase activity was markedly decreased in this patient, being approximately 12% of the mean value of normal controls (4 aged-matched healthy boys). In contrast, leukocyte delta-aminolevulinic acid (ALA) synthase activity was normal. The free protoporphyrin content of erythrocytes was greatly increased (4.3 mg/100 ml RBC), while erythrocyte ALA dehydratase and porphobilinogen (PBG) deaminase activities were 1.7- and 2.2-fold of respective control values. A survey of his family revealed that 12 of 19 members probably had manifest EPP or were EPP carriers. These results suggest that, in EPP, there might be an inherited impairement of ferrochelatase activity which gives rise to an elevation of erythroblast ALA dehydratase and PBG deaminase activities to compensate for a resultant decrease in heme production.
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PMID:Decreased leukocyte ferrochelatase activity in erythropoietic protoporphyria. 277 87

Incubation of porphobilinogen (PBG) with PBG deaminase from Rhodopseudomonas sphaeroides in carbonate buffer (pH 9.2) to total PBG consumption resulted in low yields of uroporphyrinogen I (uro'gen I). In the reaction mixture a pyrrylmethane accumulated, which at longer incubation periods was transformed into uro'gen I. The accumulated pyrrylmethane gave an Ehrlich reaction which was different from that of a 2-(aminomethyl)dipyrrylmethane or 2-(aminomethyl)tripyrrane. It resembled that of a bilane (tetrapyrrylmethane) but was different from that of a 2-(hydroxymethyl)bilane. The 13C NMR spectra of incubations carried out with [11-13C]PBG indicated that the pyrrylmethane was a tetrapyrrole with methylene resonances at 22.35-22.50 ppm. It was loosely bound to the deaminase, and when separated from the enzyme by gel filtration or gel electrophoresis, it immediately cyclized to uro'gen I. No enzyme-bound methylene could be detected by its chemical shift, suggesting that its line width must be very broad. When uro'gen III-cosynthase was added to the deaminase-tetrapyrrole complex, uro'gen III was formed at the expense of the latter in about 75% yield. The tetrapyrrole could only be partially displaced from the enzyme by ammonium ions, although a small amount of 2-(aminomethyl)bilane was always formed together with the tetrapyrrole intermediate. A protonated uro'gen I structure for this intermediate was ruled out by incubations using [2,11-13C]PBG. Uro'gen III formation from 2-(hydroxymethyl)bilane (HMB) and from the deaminase-tetrapyrrole intermediate was compared by using deaminase-cosynthase and cosynthase from several sources. It was found that while the HMB inhibited uro'gen III formation at higher concentrations and longer incubation times, uro'gen III formation from the complex did not decrease with time.
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PMID:Spectroscopic evidence for a porphobilinogen deaminase-tetrapyrrole complex that is an intermediate in the biosynthesis of uroporphyrinogen III. 326 69

The procedures for the generation of enzyme-substrate complexes from labeled porphobilinogens [(2,11-13C]PBG and [2,6,11-3H]PBG) with deaminase and the methods employed for their purification are described. Use of 13C NMR failed to detect the substrate bound to the enzyme, suggesting that the line width must be inordinately large. The complex was found to disproportionate with time when stored at 25 degrees C. However, enzyme-bound uroporphyrinogen I (uro'gen I) was detected, both in the intact protein and in the oligopeptides from tryptic digestion and peptide mapping. The first detection of an enzyme-substrate complex by 3H NMR is described for [3H]PBG and deaminase. The line widths of the observed resonances were found to be extremely large and dependent upon temperature, giving chemical shifts that suggest the involvement of a sulfhydryl group as the nucleophilic enzyme group that binds the substrate. The catalytic competence of this complex was also demonstrated by displacing bound [3H]PBG with unlabeled PBG. During the resultant formation of [3H]uro'gen I, a transient low-intensity signal was detected that has been tentatively assigned to the highly reactive azafulvene species, proposed in several mechanistic schemes for porphyrin biosynthesis.
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PMID:Biosynthesis of porphyrins and corrins. 2. Isolation, purification, and NMR investigations of the porphobilinogen-deaminase covalent complex. 348 2


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