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)

The frequency of low erythrocyte porphobilinogen deaminase (PBGD) activity was investigated in 2234 blood donors and in 30 patients with acute intermittent porphyria. The mean enzyme activities (+/- SD) were 3.38 +/- 0.58 U and 1.82 +/- 0.41 U, respectively. Eighteen blood donors without any history of symptoms of porphyria or haematological disease had low PBGD activity (less than 2.20 U), and they were studied further. All of them also had subnormal concentrations of the erythrocyte enzyme protein, as determined by an immunological method. Lymphocyte PBGD activity was within the normal range, but this parameter does exhibit a wide overlap between normal and porphyric values. Urinary excretion of porphobilinogen was moderately increased in two of the blood donors. In four of the 18 families of the blood donors with low PBGD activity several first-degree relatives had low erythrocyte enzyme activity, consistent with a dominant mode of inheritance. The 5-aminolaevulinic acid loading-test was normal in the blood donors with familial occurrence of low erythrocyte PBGD. It is concluded that inherited defects in erythrocyte PBGD occurred among Finnish blood donors with a frequency of about 1 in 500. The defects may be identical with those in acute intermittent porphyria (AIP), but other mechanisms are also possible, e.g. a mutation in the erythroid-specific part of the PBGD gene.
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PMID:Frequency of low erythrocyte porphobilinogen deaminase activity in Finland. 158 64

Changes in the level of transcripts encoding enzymes of the heme biosynthetic pathway as well as those encoding ubiquitous proteins were examined in murine Friend virus-transformed erythroleukemia cells during erythroid cell differentiation induced by chemicals including dimethyl sulfoxide (DMSO). Early changes following DMSO treatment were marked decreases in mRNAs for three ubiquitous proteins, i.e., a 70 kDa heat shock protein (less than 6 h), heme oxygenase and nonspecific delta-aminolevulinate synthase (ALAS) (less than 12 h). These changes were followed by sequential increases in mRNAs for enzymes in the heme biosynthetic pathway. Namely, mRNAs for the erythroid-specific ALAS, delta-aminolevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase started to increase at 12, 18, 18-24 and 24 h, respectively. Nuclear runoff studies revealed that these changes are largely transcriptional. Treatments with other inducers of erythroid differentiation, e.g., hexamethylene bisacetamide, n-butyric acid and N'-methylnicotinamide, also showed similar effects on mRNAs as those following DMSO. These findings suggest that both suppression of ubiquitous genes and activation of heme pathway enzyme genes are associated with erythroid differentiation, and the former occurs preceding changes in the latter.
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PMID:Sequential activation of genes for heme pathway enzymes during erythroid differentiation of mouse Friend virus-transformed erythroleukemia cells. 195 53

Heme synthesis and degradation play pivotal roles in the regulation of growth and differentiation of erythroid and non-erythroid cells. Heme synthesis in mammalian cells involves eight enzymes which are localized in mitochondrial and cytoplasmic compartments. These enzymes have been well-characterized and cDNAs for six of the enzymes has been cloned. Two enzymes in the enzymes of the heme biosynthetic pathway, delta-aminolevulinic acid synthase (ALAS) and porphobilinogen deaminase (PBG-D) have special features and may have regulatory functions in heme synthesis by hematopoietic cells. ALAS exists as two isozymes which are encoded by non-erythroid and erythroid-specific genes, respectively. By contrast, PBG-D, which also exists as two isozymes, arises from a single gene comprised of two overlapping transcriptional units, each with its own promoter. Transcription from one or the other of these promoters gives rise through differential splicing to two distinct mRNA species which encode the distinct nonerythroid and erythroid isoforms. On the other hand, heme catabolism is determined by the levels of the heme oxygenase system. The enzyme has been purified and the cDNA for heme oxygenase has been cloned. Repression of heme oxygenase in erythroid progenitor cells may initiate differentiation. In addition, recent evidence has suggested that heme may have a broader role in hematopoiesis and in the network of cytokine production by adherent stromal cells.
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PMID:Molecular regulation--biological role of heme in hematopoiesis. 203 26

Porphobilinogen deaminase, the third enzyme in the heme biosynthetic pathway, is encoded by a gene having two different promoters. Differential splicing of transcripts from the promoters yields two distinct mRNA species that are translated to give two isoforms of the protein. One isoform is ubiquitous, whereas the other is erythroid-specific. In this study, we have analyzed the gene regulatory elements that contribute to the tissue-specific promoter utilization of the mouse porphobilinogen deaminase gene. Six nuclear DNase I-hypersensitive sites were mapped in erythroid and nonerythroid cells, and four of these regions were further analyzed for in vitro nuclear protein-binding sites. The erythroid-specific promoter contains three erythroid nuclear factor GF-1-binding sites. The proximal GF-1-binding site, together with an adjacent duplicated CACCC motif, was sufficient to confer erythroid-specific expression in functional studies. Furthermore, as upstream gene sequences were shown to greatly increase promoter activity in erythroid cells, it suggests an upstream erythroid-specific enhancer may also be required for the up-regulation of the erythroid-specific promoter during erythropoiesis.
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PMID:Characterization of hypersensitive sites, protein-binding motifs, and regulatory elements in both promoters of the mouse porphobilinogen deaminase gene. 203 97

Human erythrocyte band 4.2 is a major membrane-associated protein with an important, but still undefined, role in erythrocyte survival. We previously sequenced the complete cDNA for band 4.2 and showed that the protein has a strong sequence identity with the transglutaminase family of proteins but lacks transglutaminase activity. Here we have analyzed the genomic organization of band 4.2. The band 4.2 gene is approximately 20 kilobases, consisting of 13 exons and 12 introns. Reticulocytes contain two different sized messages for band 4.2, and our results show that the major, smaller, message is produced by alternative splicing within band 4.2 exon I. The upstream region of the gene has several prospective promoter elements arranged in a pattern similar to that of two other erythroid genes, beta-globin and porphobilinogen deaminase. Alignment of the band 4.2 amino acid sequence with that of the a subunit of human coagulation factor XIII and division of the sequences into exons reveal a remarkable correspondence, and in most cases identity, in the sizes of the paired exons. Moreover, each corresponding intron of the two genes is of an identical splice junction class. These and other similarities suggest that the gene for band 4.2 is closely related to and possibly derived from that for the a subunit of factor XIII and that the proteins may share common structural and functional properties.
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PMID:Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the a subunit of factor XIII. 205 63

All nucleated animal cells synthesize heme to provide the prosthetic group of respiratory cytochromes. Large amounts of heme are synthesized by erythroid cells for hemoglobin production and by liver cells for drug-induced cytochromes P450. This review focuses on the first enzyme of the heme biosynthetic pathway, 5-aminolevulinate synthase (ALAS), which catalyzes the rate-controlling step in liver and possibly other tissues. We report that there are two distinct human genes for ALAS: one, a housekeeping gene, is probably ubiquitously expressed while the other is active only in erythroid tissue. By contrast it has been reported that, for porphobilinogen deaminase, the third enzyme of the heme pathway, there is a single human gene with two promoters; one functional in all tissues, the other erythroid specific. In liver, transcription of the housekeeping ALAS gene is induced by drugs and repressed by heme. Heme also acts in a novel way to prevent transport of ALAS into mitochondria, its site of function. Porphyrias result from inherited defects in enzymes of the heme pathway subsequent to ALAS and the molecular abnormality is now known for the most common subtype of acute intermittent porphyria. In developing red cells, levels of ALAS are regulated by increased gene transcription and by a post-transcriptional mechanism, in which iron most probably controls translation of erythroid ALAS mRNA through an iron-responsive element identified in the 5' untranslated region of the mRNA. The human erythroid ALAS gene is located on the X-chromosome, suggesting that a defect in this gene may be responsible for X-linked sideroblastic anemias.
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PMID:Molecular regulation of 5-aminolevulinate synthase. Diseases related to heme biosynthesis. 209 58

The aim of our group's work has been to elucidate how the alpha- and beta-globin genes come to be co-expressed together with a set of characteristic non-globin genes during erythroid cell differentiation. Our most significant progress concerns the identification and analysis of a species-conserved transcription factor, EF1, that appears to play a general role in the regulation of erythroid-specific gene transcription. We have shown that the 4 kb of 5' flanking region of the mouse alpha-globin gene contains two erythroid-specific cis-control elements, both of which involve EF1 binding sites. We have also identified functionally active EF1 binding sites in the mouse beta-globin promoter, as well as in the erythroid-specific promoter of the gene encoding the haem biosynthetic enzyme, porphobilinogen deaminase (PBG-D). The function of the PBG-D promoter depends in part on the cooperation between an EF1 binding site and an adjacent CACCC motif, this being abolished if their spacing is increased beyond 40 nt. We have also investigated the mechanisms involved in the up-regulation in erythroid cells of two non-globin genes we have cloned, encoding the RBC-specific lipoxygenase (LOX) and glutathione peroxidase (GSHPX). As judged by the presence of tissue-specific DNAse I hypersensitive sites, the tissue-specific regulation of the GSHPX gene seems to be due to regulatory regions 3' to the gene. The level of GSHPX is also regulated by selenium and this occurs at two levels: during mRNA formation, and during translation of the mRNA due to the regulation of selenocysteine incorporation specified by a unusual use of the UGA codon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of erythroid-specific gene expression. 211 51

Although the erythroid-specific promoter of human porphobilinogen deaminase [PBGD] gene has no TATA box, transcription is initiated at a single nucleotide. Using 5' and 3' deletions and point mutations, we have identified an element, located around the initiation site, which is necessary and sufficient for 'in vitro' accurate initiation of transcription. This 15 bp element extends 1 bp 5' and 14 bp 3' from the initiation site. It is composed of two regions, a proximal region centred on the cap site and a distal region which bears homology with the TdT initiator element. We show that a nuclear factor, present both in erythroid and non erythroid cells, binds the distal PBGD initiator element. Lack of heat inactivation suggests that initiation of transcription mediated by this element is not TFIID dependent. By transfection into erythroid cells, we also show that the proximal PBGD initiator element is essential for the selection of the initiation site but not for the regulation of transcription of the PBGD erythroid promoter during erythroid differentiation.
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PMID:Initiation of transcription of the erythroid promoter of the porphobilinogen deaminase gene is regulated by a cis-acting sequence around the cap site. 225 Nov 13

We have studied the elements involved in the tetradecanoylphorbol acetate (TPA)-mediated extinction of erythroid-specific genes. We show that transcription driven by a -714/+78-base pair DNA fragment of the erythroid promoter of the human porphobilinogen deaminase gene is down-regulated upon TPA treatment of erythroleukemic cells. Examination of the DNA binding activity of trans-acting factors involved in the expression of the porphobilinogen deaminase erythroid promoter showed (i) a constitutive expression of the CACC binding proteins and (ii) a decrease in DNA binding activity of two tissue-specific factors, NF-E1 and NF-E2. Kinetics experiments indicated that NF-E2 was down-regulated after 1 h of TPA treatment whereas NF-E1 was down-regulated at the protein and mRNA levels only after 5 h of TPA treatment. These results suggest that different pathways, acting via different transcription factors, are involved in the TPA-mediated extinction of erythroid-specific genes.
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PMID:The extinction of erythroid genes after tetradecanoylphorbol acetate treatment of erythroleukemic cells correlates with down-regulation of the tissue-specific factors NF-E1 and NF-E2. 226 12

In situ hybridization was used to study the effects of hemin on the expression of the oncogenes c-myc, c-fos, and myb, and on the mRNA level of erythroid porphobilinogen deaminase (PBG-D) and alpha-globin in HEL cells during differentiation. The technique was effective in detecting changes in mRNA levels in small numbers of HEL cells. Hemin stimulation of HEL cells results in an early increase in myb and c-myc expression and a decrease in c-fos mRNA, while increased PBG-D and alpha-globin expression is not seen until 8 h after hemin treatment. Blast-like cells display expression of c-myc, alpha-globin and PBG-D, while the more differentiated cells give a positive response to both c-fos and myb. During HEL cell differentiation, the mechanism of hemin stimulation appears to be through the up regulation of myb and c-myc mRNA and down regulation of c-fos. The subsequent expression of PBG-D and alpha-globin may indicate that early increases in protooncogene expression are first required for the normal progression of erythropoiesis to occur.
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PMID:Early protooncogene expression during hemin-induced differentiation of human erythroleukemic cells. 228 Jun 14


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