Disease relevance of porphobilinogen

• To investigate the molecular pathology in acute intermittent porphyria (AIP), the nature of the defective porphobilinogen (PBG)-deaminase was determined in erythrocyte lysates from 165 AIP heterozygotes from 92 unrelated families representing 20 different ethnic or demographic groups [1].
• Acute intermittent porphyria is an inborn error of metabolism characterized by the excretion of excess porphyrin precursors (porphobilinogen and usually delta-aminolevulinic acid) in the urine, and by sporadic attacks of neurologic dysfunction [2].
• 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 [3].
• The disease is due to mutations in the gene encoding for porphobilinogen (PBG) deaminase and is characterized by life-threatening neurovisceral attacks, often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases [4].
• Bradyrhizobium japonicum porphobilinogen synthase (B. japonicum PBGS) has been purified and characterized from an overexpression system in an Escherichia coli host (Chauhan, S., and O'Brian, M. R. (1995) J. Biol. Chem. 270, 19823-19827) [5].

High impact information on porphobilinogen

• During acute attacks delta-aminolevulinic acid and porphobilinogen also increase, suggesting that porphobilinogen deaminase (PBG-D) may be rate limiting [6].
• Two mutations of the porphobilinogen (PBG) deaminase gene resulting in cross-reacting immunological material (CRIM) positive forms of acute intermittent porphyria (AIP) have been identified by in vitro amplification of cDNA and cloning of the amplified products in a bacterial expression vector [7].
• BACKGROUND: In acute porphyria, repletion of intrahepatic heme, with exogenously administered heme, suppresses the overproduction of delta-aminolaevulinic acid (ALA) and porphobilinogen (PBG) [8].
• 5-Aminolaevulinate dehydratase (ALAD) is a homo-octameric metallo-enzyme that catalyses the formation of porphobilinogen from 5-aminolaevulinic acid [9].
• Expression and subcellular location of the tetrapyrrole synthesis enzyme porphobilinogen deaminase in light-grown Euglena gracilis and three nonchlorophyllous cell lines [10].

Chemical compound and disease context of porphobilinogen

• The diagnosis of acute intermittent porphyria was made in 10 members of a large kindred because of increased excretion of porphobilinogen and delta-aminolevulinic acid in the urine but normal fecal porphyrins [11].
• Porphobilinogen deaminase, the product of the hemC locus in Escherichia coli K12, catalyses the tetrapolymerisation of porphobilinogen (PBG) into the hydroxymethylbilane, preuroporphyrinogen [12].
• Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism [13].
• Two weeks later his urine was found to contain porphobilinogen, indicating that latent acute intermittent porphyria had been unmasked by phenobarbitone [14].
• We tested the hypothesis that the hyponatremia commonly observed in patients with acute hepatic porphyria is mediated by the presence of aminolaevulinic acid (ALA) and (or) porphobilinogen (PBG) at the level of the renal tubule to alter water handling, or at the level of the nervous system to release antidiuretic hormone (ADH) [15].

Biological context of porphobilinogen

• A common two-allele MspI restriction fragment length polymorphism of the human erythroid porphobilinogen (PBG)-deaminase gene was investigated in 33 unrelated patients with acute intermittent porphyria (AIP) and 20 controls [16].
• Plasmids containing DNA from the green photosynthetic bacterium Chlorobium vibrioforme complement a heme-requiring Escherichia coli hemB mutant that is deficient in porphobilinogen (PBG) synthase activity [17].
• Newly synthesized analogues of a reaction intermediate of porphobilinogen synthase have been employed in studying the active site and the catalytic mechanism of this early enzyme of tetrapyrrole biosynthesis [18].
• Porphobilinogen synthase from pea: expression from an artificial gene, kinetic characterization, and novel implications for subunit interactions [19].
• Purification of porphobilinogen deaminase from Euglena gracilis and studies of its kinetics [20].

Anatomical context of porphobilinogen

• Uroporphyrinogen I (URO) synthase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] activity increased when cultures of normal human bone marrow cells were incubated with erythropoietin [21].
• Rabbit reticulocyte ALA-D is about as active in converting delta-aminolevulinic acid to porphobilinogen and as Zn2+-dependent as ALA-D purified from other sources [22].
• 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 [23].
• Diagnostic laboratory tests include quantitation of delta ALA, porphobilinogen, and porphyrins in blood, urine, and feces and analysis of activities of enzymes of the heme-forming system [24].
• Ontogeny of 5-aminolevulinic dehydratase and porphobilinogen deaminase activities in the yolk sac membrane and liver of chick embryos [25].

Associations of porphobilinogen with other chemical compounds

• 5-Aminolevulinic acid dehydratase (ALAD), an early enzyme of the tetrapyrrole biosynthesis pathway, catalyzes the dimerization of 5-aminolevulinic acid to form the pyrrole, porphobilinogen [26].
• Porphobilinogen deaminase (PBG-D), an early enzyme of the tetrapyrrole biosynthetic pathway, catalyzes the formation of a tetrapyrrole chain, preuroporphyrinogen, from four molecules of porphobilinogen (PBG) [27].
• The discs are incubated with porphobilinogen (0.11 mmol/liter) in tris(hydroxymethyl)aminomethane HCl buffer, pH 8.2, in the dark at 37 degrees C for 3.5 h [28].
• After the hemolysates are incubated with porphobilinogen, the porphyrins are converted to their methyl esters and examined by liquid chromatography, with fluorometric detection [29].
• 3. The stoicheiometry of the overall reaction at pH 7.4 was shown to be: 4 Porphobilinogen leads to uroporphyrinogen-I + 4 NH4+ [20].

Gene context of porphobilinogen

• It is not the proposed hemB gene product porphobilinogen synthase [30].
• Earlier reports have suggested that expression of HEM3 is induced by porphobilinogen, the substrate of the encoded enzyme [31].
• The cloned gene showed high levels of nucleic acid and protein sequence homology to the HEM2 genes, encoding porphobilinogen synthases, from several sources [32].
• 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 [33].
• ALAD is a cytoplasmic enzyme that catalyzes the second step of the heme biosynthesis pathway, that is, the condensation of two molecules of delta-aminolevulinic acid into porphobilinogen [34].

Analytical, diagnostic and therapeutic context of porphobilinogen

• An isoelectric focusing method for detection of structural variants of the enzyme uroporphyrinogen I synthase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in mammalian tissues has been developed [35].
• This report describes a prospective study on the molecular epidemiology of PBG deaminase gene defects in AIP [4].
• Transmission electron microscopy showed a correlation between the ultrastructural pathology of the liver, the total porphyrin levels in urine and liver, and the porphobilinogen levels in urine [36].
• Dissection of the early steps in the porphobilinogen synthase catalyzed reaction. Requirements for Schiff's base formation [37].
• A micellar electrokinetic capillary chromatographic (MECC) method has been developed and optimised for the separation of 5-aminolaevulinic acid (ALA) and porphobilinogen (PBG) [38].

References