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)

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

A 3.8-kilobase DNA fragment from Bacillus subtilis containing the hemA gene has been cloned and sequenced. Four open reading frames were identified. The first is hemA, encoding a protein of 50.8 kilodaltons. The primary defect of a B. subtilis 5-aminolevulinic acid-requiring mutant was identified as a cysteine-to-tyrosine substitution in the HemA protein. The predicted amino acid sequence of the B. subtilis HemA protein showed 34% identity with the Escherichia coli HemA protein, which is known to code for the NAD(P)H:glutamyl-tRNA reductase of the C5 pathway for 5-aminolevulinic acid synthesis. The B. subtilis HemA protein also complements the defect of an E. coli hemA mutant. The second open reading frame in the cloned fragment, called ORF2, codes for a protein of about 30 kilodaltons with unknown function. It is not the proposed hemB gene product porphobilinogen synthase. The third open reading frame is hemC, coding for porphobilinogen deaminase. The fourth open reading frame extends past the sequenced fragment and may be identical to hemD, coding for uroporphyrinogen III cosynthase. Analysis of deletion mutants of the hemA region suggests that (at least) hemA, ORF2, and hemC may be part of an operon.
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PMID:Cloning and characterization of the hemA region of the Bacillus subtilis chromosome. 211 Jan 38

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

Porphyria cutanea tarda (PCT) results from a metabolic block in heme synthesis at the level of uroporphyrinogen decarboxylase. We measured the activity of one of the enzymes preceding it in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD; EC 4.3.1.8), in erythrocytes of 47 patients with symptomatic or asymptomatic familial or sporadic PCT. PBGD activity was significantly increased in all four PCT groups, compared with controls. To study the mechanism of this increased PBGD activity, we determined, using polyclonal antibodies, the amount of immuno-detectable PBGD per 100 units of PBGD activity (Ig PBGD/100 U) and the total amount of immuno-detectable PBGD (Ig PBGD) in erythrocytes from all 47 patients and from controls. In both familial and sporadic PCT, Ig PBGD/100 U was decreased compared with that in controls (P less than 0.05). Especially in asymptomatic patients of the familial PCT group there was an inverse correlation between increasing PBGD activity and Ig PBGD/100 U (r = -0.90). In familial PCT, and to a minor degree in sporadic PCT, an increase in PBGD activity was accompanied by an increased Ig PBGD, compared with controls (familial PCT: P less than 0.001, sporadic PCT: P less than 0.05). In familial and sporadic PCT an increase in erythrocyte PBGD activity can, at least partly, be explained by a diminished degradation of PBGD. In familial PCT, in the symptomatic group more than in the asymptomatic group, and to a minor degree in sporadic PCT, there is in addition an increase in the absolute amount of PBGD.
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PMID:Erythrocyte porphobilinogen deaminase activity in porphyria cutanea tarda. 220 54

Hereditary deficiency of complement component C3 in a 10-yr-old boy was studied. C3 could not be detected by RIA of serum from the patient. Segregation of C3 S and C3 F allotypes within the family confirmed the presence of a null gene for C3, for which the patient was homozygous. 30 exons have been characterized, spanning the entire beta chain of C3 and the alpha chain as far as the C3d region. Sequence analysis of the exons derived from the C3 null gene showed no abnormalities in the coding sequences. A GT-AT mutation at the 5' donor splice site of the intervening sequence 18 was found in the C3 null gene. Exons 17-21 were amplified by the polymerase chain reaction (PCR) from first-strand cDNA synthesized from mRNA obtained from peripheral blood monocytes stimulated with LPS. This revealed a 61-bp deletion in exon 18, resulting from splicing of a cryptic 5' donor splice site in exon 18 with the normal 3' splice site in exon 19. This deletion leads to a disturbance of the reading frame of the mRNA with a stop codon 17 bp downstream from the abnormal splice in exon 18. His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR. Similar splice mutants have previously been reported in the beta-globin, phenylalanine hydroxylase, and porphobilinogen deaminase genes. This mutation is sufficient to cause the deficiency of C3 in the patient.
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PMID:Molecular basis of hereditary C3 deficiency. 221 5

A basal level of human liver porphobilinogen deaminase of 3.66 units/g wet weight was found in adult tissue. Activity in neonatal liver was at least three fold higher. Physico-chemical studies revealed that the enzyme has the approximate form of a symmetrical molecule and exhibits hyperbolic kinetics with a Km value of 3.6 microM at pH 7.6. Two ionizable groups with pK values of 7.35 and 8.90 are prominent for catalysis. A set of pI (5.8-4.9) were observed under different conditions. Results demonstrate the existence of a single protein differentially charged with multiple molecular forms in adult liver.
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PMID:Kinetic and molecular parameters of human hepatic porphobilinogen deaminase. 222 91

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

A method for isolating pure reticulocytes from leukocyte-depleted blood of normal persons is presented. The separation was achieved using an immunomagnetic technique. A monoclonal mouse antibody against human transferrin receptor was bound to magnetic beads conjugated with sheep antimouse antibody. The recovery of reticulocytes from peripheral blood was 15% to 42%. Blood used for isolation of reticulocytes could be stored for 4 days at 22 degrees C without altering the yield of reticulocytes. At 37 degrees C incubation, the reticulocytes matured rapidly and the transferrin receptor was found to have a half-life of 16 hours. The activity of several enzymes and the amount of creatine and hemoglobin A1C were measured both in the reticulocytes and peripheral blood. Of the enzymes, porphobilinogen deaminase had the best discriminatory power with a ratio of 8.8 between reticulocytes and peripheral red blood cells. The ratio for creatine was 16.7. The ability to isolate pure human reticulocytes, released after normal erythropoiesis, will offer new possibilities in the study of these cells.
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PMID:A new method for isolation of reticulocytes: positive selection of human reticulocytes by immunomagnetic separation. 225 9

The progesterone receptor gene (PGR), the gene coding for porphobilinogen deaminase (PBGD), the gene coding for a neural cell adhesion molecule (NCAM), the oncogene ETS1, and the anonymous genomic sequence D11S29 have been previously located on the long arm of chromosome 11. However, gene localizations obtained with different gene-mapping procedures have led to occasional discrepancies. To localize these genes more precisely, we hybridized five human DNA sequences with different chromosomal rearrangements, including four balanced and one unbalanced translocations. We show here that the order of these five sequences is cen-PGR-PBGD-DIIS29/NCAM/ETS1-tel.
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PMID:Fine mapping of the long arm of human chromosome 11 by in situ hybridization using different translocations, including the t(11;22) of Ewing sarcoma. 226 56

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


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