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)

Porphobilinogen deaminase, the third enzyme of the haem biosynthetic pathway, is encoded by two distinct mRNA species expressed in a tissue-specific manner from a single gene. These two mRNAs are transcribed from two promoters and only differ in their first exon. An inherited deficiency or porphobilinogen deaminase in man is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. In the present report, we describe the molecular abnormality responsible for a variant form of acute intermittent porphyria where the enzyme defect is restricted to non-erythroid cells. Upon cloning and sequencing the mutant allele of a patient from a large Finnish kindred, a single-base substitution within the 5'-splice donor sequence of intron 1 was found at the last position of exon 1 (CG----CT). The identification of this mutation allowed us to detect asymptomatic gene carriers among family members using in vitro amplification of DNA and hybridization of the target sequence to allele-specific oligonucleotides.
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PMID:Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase. 251 Oct 16

The human gene coding for porphobilinogen deaminase (PBG-D) is transcribed into two distinct transcription units giving two mRNAs. These units originate from two adjacent promoters distant of 3 kilobase pairs. The upstream promoter is active in all cell types, whereas the downstream promoter is active only in erythroid cells. We have studied the expression of this gene either after introduction of the corresponding human chromosome into murine erythroid cells using somatic hybrids or after transfection into both erythroid and non-erythroid cells. Using somatic hybrids, we showed that activation of the erythroid-specific promoter of the PBG-D gene did not reduce the rate of initiation of the ubiquitous promoter. Transfection experiments in erythroid cells showed that the PBG-D erythroid transcription unit, controlled by the PBG-D erythroid promoter, was correctly transcribed and regulated. Furthermore, we found that the PBG-D erythroid promoter alone was sufficient for correct expression and regulation of a reporter gene during erythroid differentiation. When the human PBG-D gene was transfected into non-erythroid cells, only the ubiquitous promoter was active. Deletion of the ubiquitous promoter did not lead to any activation of the erythroid promoter, suggesting that its inactivity in non-erythroid cells was not due to promoter occlusion but to a strict erythroid specificity.
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PMID:Regulated expression of the overlapping ubiquitous and erythroid transcription units of the human porphobilinogen deaminase (PBG-D) gene introduced into non-erythroid and erythroid cells. 254 27

An inherited deficiency of porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in humans is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. It was previously demonstrated that porphobilinogen deaminase is encoded by two distinct mRNA species expressed in a tissue-specific manner. Analysis of the genomic sequences indicated that these two mRNAs are transcribed from two promoters and only differ in their first exon. The first mutation identified in the human porphobilinogen deaminase gene is a single-base substitution (G----A) in the canonical 5' splice donor site of intron 1. This mutation leads to a particular subtype of acute intermittent porphyria characterized by the restriction of the enzymatic defect to nonerythropoietic tissues. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offers another possibility of detecting asymptomatic carriers of the mutation in affected families.
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PMID:Tissue-specific splicing mutation in acute intermittent porphyria. 256 67

To study the existence of different mutations in acute intermittent porphyria, erythrocyte porphobilinogen deaminase activity and enzyme protein concentration were investigated in 125 porphyria gene carriers from 31 families, and in 121 apparently healthy controls. Porphobilinogen deaminase concentration (micrograms/gHb) was quantified using a recently developed double-sandwich ELISA. The ratio of enzyme catalytic activity to the concentration of enzyme protein was expressed as the porphobilinogen specific activity (nkat/g). The controls had a mean porphobilinogen deaminase concentration of 160 +/- 35 micrograms/gHb and a specific activity of 762 +/- 127 nkat/g. Two different types of mutation causing acute intermittent porphyria were detected. The majority (91%) of gene carriers, from 25 families, had a diminished porphobilinogen deaminase concentration of 102 +/- 18 micrograms/gHb, with a slightly lowered specific activity of 634 +/- 105 nkat/g. In 9% of the gene carriers, representing six different families, an increase in porphobilinogen deaminase concentration to 269 +/- 46 micrograms/gHb, and a highly significant reduction in specific activity to 234 +/- 48 nkat/g, were found, which indicates the presence of a different mutation.
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PMID:Mutations in acute intermittent porphyria detected by ELISA measurement of porphobilinogen deaminase. 260 15

Porphobilinogen deaminase was purified from human erythrocytes by ion-exchange chromatography, gel filtration and hydrophobic interaction chromatography. Two forms of the enzyme were isolated, with apparent molecular weights of 40 kDa and 42 kDa, and in relative amounts of 85% and 15%, respectively. Both forms were found to have an N-terminal amino acid sequence identical to that published for the erythropoietic form of porphobilinogen deaminase, as deduced from a cDNA clone. The two forms present could each be separated into three differently charged subforms by Mono Q chromatography.
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PMID:Porphobilinogen deaminase in human erythrocytes: purification of two forms with apparent molecular weights of 40 kDa and 42 kDa. 260 11

Expression of porphobilinogen deaminase in a hemB- strain of E. coli has permitted the isolation of the apoenzyme, i.e. deaminase lacking the porphobilinogen-derived dipyrromethane cofactor. Incubation of purified apoenzyme with porphobilinogen resulted in reconstitution of the covalently attached dipyrromethane cofactor, indicating no additional cofactors or enzymes are required for biosynthesis of holoenzyme. Electrophoretic and 13C-NMR spectroscopic analyses demonstrate that the apoenzyme exists in a conformationally unstable form which is converted to a highly stable tertiary structure on covalent attachment of the dipyrromethane cofactor.
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PMID:Reconstitution of apo-porphobilinogen deaminase: structural changes induced by cofactor binding. 264 32

A coexistent dual deficiency of porphobilinogen deaminase (PBG-D; EC 4.3.1.8) and uroporphyrinogen decarboxylase (EC 4.1.1.37) in erythrocytes was recognized in five individuals, four males and one female. Clinically, the female and one male were diagnosed as suffering from acute intermittent porphyria (AIP), and the other two males were diagnosed as having porphyria cutanea tarda (PCT). Biochemically, the excretion pattern of urinary and fecal heme precursors exhibited a complex constellation with signs characteristic for both AIP and PCT. A coexistent dual enzyme deficiency of PBG-D and URO-D could be confirmed by repeated studies over 10 years. Clinical courses of both disease manifestations were observed. Family investigations have shown that the two disorders do not consistently segregate together. The findings suggest that the dual porphyria reflects a double heterozygous condition of coexistent AIP and PCT genes in the same individual.
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PMID:Dual porphyria in double heterozygotes with porphobilinogen deaminase and uroporphyrinogen decarboxylase deficiencies. 272 Oct 23

The porphobilinogen deaminase gene encodes the third enzyme of the heme biosynthetic pathway. This gene is expressed in a tissue-specific manner and gives rise to two isoenzymatic forms encoded by mRNA species differing in their 5' extremity. Recent studies in human demonstrated that the tissue-specific expression of the porphobilinogen deaminase gene is determined in erythropoietic cells, by the utilization of a specific promoter situated 3' to the housekeeping promoter used in other cell types. This results, through differential splicing, in the mutually exclusive presence of either exon 1 or exon 2 in mature mRNAs. Here, we report the cloning and sequencing of the porphobilinogen deaminase gene from mouse. The overall organization of the mouse gene is similar to that of the human one. In the housekeeping promoter, only a short stretch of homology is found including two potential Sp1 binding sites; in contrast, more extensive similarity appears in the erythroid-specific promoter including two motifs also found in globin gene, a CACCC box, and a recently described Ery F1 consensus binding sequence. We derived a set of single-stranded probes corresponding to different parts of the mouse gene to carry out a detailed analysis of the transcriptional unit in various cell types, using a run-on transcription assay on isolated nuclei. In liver cells, the first (non-erythropoietic) exon is more actively transcribed than parts of the gene situated downstream, suggesting that the elongation of transcripts is blocked within the 5' part of the first intron. In erythropoietic cells, the downstream promoter becomes activated; surprisingly, the initiation of transcription is also enhanced from the upstream (housekeeping) promoter and most of the transcripts initiated at the housekeeping promoter stop downstream of the first exon, between the two promoters.
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PMID:The mouse porphobilinogen deaminase gene. Structural organization, sequence, and transcriptional analysis. 276 42

Two cis-acting sequences, recognized by two erythroid-specific trans-acting factors, are involved in the regulation of the erythroid promoter of the human gene coding for porphobilinogen deaminase (PBGD). The first region, located at -70, binds the erythroid factor NF-E1, and point mutations within this region abolish the induction of transcription of this promoter during murine erythroleukemia (MEL) cell differentiation. The second region, located at -160, binds the erythroid-specific factor NF-E2 and the ubiquitous factor AP1. Using UV cross-linking, we show that NF-E2 has a higher molecular weight than AP1, demonstrating that NF-E2 is not an erythroid-specific degradation product of AP1. By point mutagenesis of the NF-E2/AP1 binding site, we define mutations that abolish binding of either NF-E2 alone or AP1 and NF-E2 together. Regulation of transcription of the PBGD erythroid promoter is abolished by those mutations, suggesting that NF-E2 but not AP1 is necessary for correct regulation of this promoter in erythroid cells.
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PMID:Cis- and trans-acting elements involved in the regulation of the erythroid promoter of the human porphobilinogen deaminase gene. 277 41

We have determined the mutation in a patient with acute intermittent porphyria. The mRNA coding for porphobilinogen deaminase was reverse transcribed then the cDNA was enzymatically amplified in vitro. Upon sequencing of a polymerase chain reaction product of abnormal size we found that this fragment lacked exon 12 of the gene. We analysed a genomic fragment containing exon 12 and determined that the patient was heterozygous for a point mutation G A at the last position of exon 12. We propose that this base change is responsible for an abnormal processing of the mutant allele such that exon 12 is missing in the mature mRNA. The resulting aberrant mRNA encodes a truncated protein which is inactive but stable and can be detected using antibodies directed against the normal enzyme.
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PMID:A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria. 278 72


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