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:2.5.1.61 (porphobilinogen deaminase)
637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute intermittent porphyria (AIP) results from mutations in the porphobilinogen deaminase (PBG) gene. Three of 14 randomly selected, unrelated patients with the cross reacting immunological material (CRIM) negative form of AIP were found to have previously undescribed RNA splicing defects. Defective splicing of exons 12 and 13 was caused by a C-->G transversion at position -3 of the 3' splice site of intron 11 and a G-->A transition at the first position of intron 13, respectively. Defective splicing of exon 3 was associated with a synonymous codon mutation (CGC-->CGG, R28R) at position -22 from the 5' splice site. Our findings are consistent with previous reports indicating that about 15% of mutations in the PBG deaminase gene that cause AIP affect RNA splicing and add to the evidence that synonymous intraexonic codon mutations may cause disease.
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PMID:Acute intermittent porphyria caused by defective splicing of porphobilinogen deaminase RNA: a synonymous codon mutation at -22 bp from the 5' splice site causes skipping of exon 3. 873 62

Three patients from Moroccan kindreds with acute intermittent porphyria (AIP) are described. The propositus of family A originating from Mrirt, Morocco, is living in Embrun, France. This 26 year-old woman who experienced an acute attack with visceral manifestations presented an elevated urinary level of 5-ALA and PBG, and a half-normal activity in porphobilinogen deaminase (PBG-D) in red blood cells (RBC). The family's survey was carried out by measuring the PBG-D activity in RBC (normal values = 125 +/- 40 U). Three of the 16 subjects tested, beside the propositus, were found to be asymptomatic carriers (PBG-D < 70 U). The two patients of family B, originating from Tetouan in the Rif area, were living in Bastia, Corsica. The two brothers, respectively 37 and 39 years old, had a long history (6 years) of neuropsychiatric manifestations before the AIP diagnosis was evidenced by elevated urinary level of 5-ALA and PBG, and showed a partial deficiency, approximately, 50%, of PBG-D activity in RBC. The youngest patient also presented a peripheral neuropathy and recently died after surgery from an unknown reason at the age of 45.
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PMID:[Acute intermittent porphyria in 2 Moroccan families. Clinical and biological study]. 875 36

The enzyme porphobilinogen deaminase (PBG deaminase, EC 4.3.1.8) catalyzes the condensation of four molecules of PBG to give the linear tetrapyrrol, hydroxymethylbilane. It has been shown that this enzyme forms stable mono-, di-, tri- and tetrapyrrole-enzyme covalent complexes. When the enzyme, partially purified in the absence or presence of phenylmethylsulfonyl fluoride (PMSF) and preincubated with PBG, was applied on DEAE-cellulose columns, three peaks with PBG deaminase activity were detected. Using Ehrlich's reagent, it was found that the active peaks corresponded to mono-, di- and tri-pyrrylmethane-enzyme complexes. Therefore, the mechanism of action of PBG deaminase from Saccharomyces cerevisiae also involves the sequential addition of four PBG units, leading to the formation of the enzyme-substrate intermediate complexes, as has already been described for the same enzyme from other sources.
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PMID:Yeast porphobilinogen deaminase also forms enzyme-pyrrole intermediates. 879 72

The complete nucleotide sequence of a 39,090 bp segment from the left arm of yeast chromosome IV was determined. Twenty-one open reading frames (ORFs) longer than 100 amino acids and a Gly-tRNA gene were discovered. Nine of the 21 ORFs (D0892, D1022, D1037, D1045, D1057, D1204, D1209, D1214, D1219) correspond to the previously sequenced Saccharomyces cerevisiae genes for the NAD-dependent glutamate dehydrogenase (GDH), the secretory component (SHR3), the GABA transport protein (UGA4), the high mobility group-like protein (NHP2), the hydroxymethylbilane synthase (HEM3), the methylated DNA protein-cysteine S-methyltransferase (MGT1), a putative sugar transport protein, the Shm1 protein (SHM1) and the anti-silencing protein (ASF2). The inferred amino acid sequences of 11 ORFs show significant similarity with known proteins from various organisms, whereas the remaining ORF does not share any similarity with known proteins.
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PMID:The nucleotide sequence of a 39 kb segment of yeast chromosome IV: 12 new open reading frames, nine known genes and one genes for Gly-tRNA. 904 97

Properties of purified porphobilinogen deaminase (PBG-D; EC 4.3.1.8) from rat harderian gland are here presented. The enzyme behaves as a monomer of Mr 38 +/- 2 kDa and is optimally active at pH 8.0-8.2. Its activation energy, determined by an Arrhenius plot, is 76.1 kJ/mol. Initial velocity studies showed a linear progress curve for uroporphyringen I formation and a hyperbolic dependence of the initial rate on substrate concentration, indicating the existence of a sequential displacement mechanism. Apparent kinetic constants, Km and Vm, calculated at 37 degrees C and pH 8.0 were 1.1 microM and 170 pmol/min mg, respectively. The pH dependence of the apparent kinetic parameters revealed the ionization of residues with pKAES and pKBES of 7.4 +/- 0.1 and 8.6 +/- 0.1, respectively, and a pKE value of 8.0 +/- 0.1. Incubation of PBG-D with 5.0 mM N-ethylmaleimide and 5.0 mM 5,5'-dithiobis(2-nitrobenzoic acid) at pH 8.0 led to inhibitions of 70 and 50%, respectively. The effect of pH, as well as the effect of thiol reagents, on enzyme activity strongly suggests the involvement of cysteine residue(s) in the mechanism of uroporphyrinogen I biosynthesis, in both the catalytic reaction and the substrate binding. Rat harderian gland PBG-D activity decreased with increasing concentrations of protoporphyrin IX, reaching a 40% inhibition at the in vivo concentration of the porphyrin and 7 microM PBG. Even at saturating concentrations of substrate, inhibition by protoporphyrin was not completely reversed. So, accumulated porphyrin may act as an regulator of PBG-D activity in rat harderian gland.
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PMID:Rat harderian gland porphobilinogen deaminase: characterization studies and regulatory action of protoporphyrin IX. 934 66

Effect of vitamin C supplementation in restoring lead induced alterations in hematopoietic system and drug metabolizing enzymes were investigated in male rats. Intraperitoneal administration of 20 mg/kg lead produced a significant inhibition of heme synthesis in blood and liver and drug metabolism in liver. Toxic insult by lead also resulted into a marked decline in tissue thiols and vitamin C levels. Oral supplementation of vitamin C (100 mg/kg for 3 days) completely restored blood delta aminolevulinic acid dehydratase, uroporphyrinogen I synthetase and a few drug metabolizing enzymes. Level of vitamin C and sulfhydryl contents too recovered to a great extent. A marked reduction in blood and liver lead concentration occurred on vitamin C supplementation although renal lead contents were marginally reduced in lead exposed animals. The results, thus, indicate a significant protective action of vitamin C against toxic effects of lead on heme synthesis and drug metabolism.
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PMID:Lead induced disorders in hematopoietic and drug metabolizing enzyme system and their protection by ascorbic acid supplementation. 955 98

5-Aminolevulinate dehydrase (ALA-D) and porphobilinogen deaminase (PBG-D) are cytosolic enzymes involved in heme biosynthesis. ALA-D activity is altered both genetically and by the action of various environmental factors, including exposure to lead. The activity of PBG-D is reduced in acute intermittent porphyria. The aim of this work is to establish the 95% reference range of the erythrocytic activity of ALA-D and PBG-D in a control population. ALA-D activity limits were 15.8 and 50.2 nmol of PBG/ml of red blood cells (RBCS) per minute. For the activity of ALA-D restored by addition of zinc and dithiothreitol ("restored ALA-D"), these limits were 44.1 and 86.5 units. It has been found that the "restored ALA-D"/ALA-D ratio is very useful for the evaluation of lead toxicity, and its 95% reference range was between 1.22 and 3.06. It has been demonstrated that the best method for measuring erythrocytic PBG-D is using PBG, but not ALA, as substrate; its 95% reference range was between 20.9 and 63.2 nmol of uroporphyrin/ml of RBCs per hour. Knowledge of these reference range values in a control population constitutes the basis for an accurate diagnosis of heavy metal intoxication and acute intermittent porphyria.
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PMID:Reference values of 5-aminolevulinate dehydrase and porphobilinogen deaminase in the Spanish population from Madrid. 957 Sep 6

Acute intermittent porphyria (AIP), the most common hepatic porphyria, results from the half-normal activity of hydroxymethylbilane synthase (HMB-synthase; EC 4.3.1.8), the third enzyme in the heme biosynthetic pathway. Because life-threatening acute neurologic attacks of this autosomal dominant disease are triggered by various ecogenic factors (e.g., certain drugs, hormones, alcohol, and starvation), efforts have been directed to identify and counsel presymptomatic heterozygotes in affected families to avoid the precipitating factors. Thus, to determine the nature of the mutations causing AIP in 26 unrelated enzyme-confirmed patients from Argentina, a long-range polymerase chain reaction method was developed to amplify the entire 10-kb gene in two fragments for efficient cycle sequencing and mutation detection. Eight new mutations were identified including two missense mutations (Q34P and G335S), four small deletions (728delCT, 815delAGGA, 948delA, and 985del12), a single base insertion (666insA), and a splice site mutation (IVS12(+1)). In addition, five previously reported mutations (G111R, R173W, Q204X, R201W, and 913insC) were detected. Notably, G111R was identified in 12 of the 26 (46%) presumably unrelated propositi; however, haplotype analysis with intragenic and flanking markers indicated an ancestral founder. Expression of the two new missense mutations (Q34P and G335S) in f1 E. coli resulted in 2.5% or less of the normal expressed enzyme, confirming their defective function. Thus, eight new and five previously reported HMB-synthase mutations, including a common lesion, were detected, permitting accurate identification and counseling of presymptomatic carriers in these 26 unrelated Argentinean AIP families with this dominant porphyria.
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PMID:Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation. 1049 93

1. Chick embryos of 7, 9, 11, 12, 13, 14, 15, 17 and 19 d of embryonic development were examined to determine the activities of 5-aminolevulinic dehydratase (ALA-D, EC 4.2.1.24) and porphobilinogen deaminase (PBG-D, EC 4.3.1.8). 2. Liver and yolk sac membrane ALA-D specific activities showed a maximum between 12 and 13 d of embryonic development, yolk sac membrane PBG-ase activity a maximum at 9 d and at 7 d in liver. Total activities of ALA-D and PBG-D were not constant during the course of embryonic development but probably related to the changes of intensity of haem synthesis. 3. ALA-D and PBG-ase activities were higher in yolk sac membrane than in liver, showing the importance of the yolk sac membrane as erythropoietic tissue. PBG-D catalysed the rate-limiting reaction of the cytosolic steps in the biosynthetic pathway in both tissues.
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PMID:Ontogeny of 5-aminolevulinic dehydratase and porphobilinogen deaminase activities in the yolk sac membrane and liver of chick embryos. 1204 82

To find an explanation for survival of homozygous or compound heterozygous variants of acute intermittent porphyria, we studied the three mutant forms of porphobilinogen deaminase (PBG-d) described in the four reported patients with homozygous acute intermittent porphyria. Wild-type human PBG-d and the PBG-d R167W, R167Q and R173Q mutants were expressed in Escherichia coli and the recombinant mutant human enzyme were examined for enzyme activity. Specific antibodies against human PBG-d detected the three human PBG-d mutants. All three had less than 2% of wild-type enzyme activity when examined under customary assay conditions (pH 8.0), but the R167W and R167Q mutants were found to have about 25% of normal activity when assayed at pH 7.0. This residual activity at a more physiological pH provides an explanation for survival when these mutations are inherited in a homozygous or compound heterozygous fashion.
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PMID:Residual activity of human porphobilinogen deaminase with R167Q or R167W mutations: an explanation for survival of homozygous and compound heterozygous acute intermittent porphyrics. 1269 44


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