Porphobilinogen and porphyrin synthesis in reticulocytes from uraemic patients.
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Abstract:
Since no information exists concerning porphyrin metabolism in uraemic patients we have measured the activities of delta-aminolaevulinic acid dehydrase (D-ALA-D) and porphobilinogen desaminase (PBG-D) in reticulocytes from uraemic patients, anaemic patients without uraemia and in healthy subjects. Despite a severe anaemia uraemic patients had the same amount of reticulocytes/mul blood. In uraemic patients D-ALA-D activity was reduced to about 20% compared to healthy subjects, PBG-D in uraemia was decreased to about 70%. It is concluded that porphyrin metabolism is altered in uraemic patients.Keywords:
Porphobilinogen
Uremia
Porphobilinogen synthase
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Changes in porphyrin metabolism attributable to diethyl-1 ,4dihydro-2,4,6-trimethylpyridine-3,5-dicarboxylate (DTD)’ were first reported by Solomon and Figge in 1959 (I, 2). After the oral administration of the compound to mice and guinea pigs, increased concentrations of liver coproporphyrin and protoporphyrin and renal uroporphyrin and protoporphyrin were observed. Urine analyses revealed increased coproporphyrin, traces of porphobilinogen, and no significant change in uroporphyrin. Such observations on the effects of DTD are of added interest when considered in light of the extensive work that has been done on experimental porphyria induced by Sedormid and related compounds. Recently, comparisons have been made of the changes in porphyrin metabolism due to DTD with alterations found in Sedormidor 2-allyl-2-isopropylacetamide-induced porphyria. The conclusions, which were based largely on porphyrin and precursor excretion patterns, were in disagreement as to the manner in which these different compounds affected porphyrin metabolism. Haeger-Aronsen (3) suggested that DTD-induced porphyria in rabbits differed from Sedormidinduced porphyria, principally in terms of a greater urinary cscretion of &aminolevulinic acid. deMatteis and Prior (4), on the other hand, concluded that the experimental porphyrias induced by DTD and Sedormid in rats were probably indistinguishable. In other reports, concerned primarily with b-aminolevulinic acid synthesis (5, 6), DTD has simply been referred to as a porphyria-inducing agent and is presumed to act like Sedormid and related compounds. However, an examination of the DTD molecule reveals that the essential groupings to induce a 2-allyl-2-isopropylacetamide or Sedormid type of porphyria are absent, and on this basis a different metabolic effect might be expected (7-10). For these reasons, a further investigation of DTD was carried out, but in this instance added emphasis has been placed on metabolism within the liver cell and on subcellular fractions. The results obtained indicate that the inhibition of iron-protoporphyrin chelation is at least one site of action of the compound. Some effects on porphyrin and iron metabolism are compared with those found in 2-allyl-2-isopropylacetamideinduced porphyria.
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Ferrochelatase
Porphobilinogen synthase
Porphobilinogen
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This thesis deals with hereditaryd iseasesin the synthesiso f heme. Heme presents a prosthetic group in a number of important proteins, like hemoglobin, cytochromes and the cytochrome P450 oxidases. In chapter 1 the heme synthesis and its regulation are described. Intermediary products in the synthesis of heme are 8-aminolevulinic acid, porphobilinogen, and series of compounds called porphyrinogens and porphyrins. Zie: Summary
Porphobilinogen
Hemeprotein
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Porphobilinogen synthase
Porphobilinogen
Porphobilinogen deaminase
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Since no information exists concerning porphyrin metabolism in uraemic patients we have measured the activities of delta-aminolaevulinic acid dehydrase (D-ALA-D) and porphobilinogen desaminase (PBG-D) in reticulocytes from uraemic patients, anaemic patients without uraemia and in healthy subjects. Despite a severe anaemia uraemic patients had the same amount of reticulocytes/mul blood. In uraemic patients D-ALA-D activity was reduced to about 20% compared to healthy subjects, PBG-D in uraemia was decreased to about 70%. It is concluded that porphyrin metabolism is altered in uraemic patients.
Porphobilinogen
Uremia
Porphobilinogen synthase
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Abstract 5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients’ enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. After this therapy both urinary 5-aminolevulinic acid (ALA) and total porphyrins were diminished to 65% in patient B. In patient H, ALA was decreased to 80%, and total porphyrins were reduced to 15% after treatment with heme arginate and glucose. The patients remained free of symptoms after this therapy. Family studies of patient B showed cross-reactive immunological material (CRIM), in which the maternal mutation is CRIM(+), whereas the paternal mutation is CRIM(−). Incubation of erythrocyte lysates with ALA decreased porphyrin formation, whereas incubation with porphobilinogen produced porphyrin concentrations within reference values in both patients, confirming that ALAD activity is rate-limiting in these cells.
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There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement.
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RECENT advances in the knowledge of porphyrin biochemistry have shown that porphobilinogen is a normal intermediate compound in the synthesis of the protoporphyrin of heme.1 , 2 Porphobilinogen results first from the combination of succinic acid and glycine to form δ-aminolevulinic acid; two molecules of this compound condense in turn to form porphobilinogen (Fig. 1),2 , 4 As shown by the work of Gibson et al.,5 porphobilinogen is the precursor not only of protoporphyrin but also of uroporphyrin and coproporphyrin. It has been suggested that uroporphyrin and coproporphyrin are by-products of the synthesis of protoporphyrin from porphobilinogen.6 In another view, uroporphyrin and coproporphyrin may . . .
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In this article I shall discuss the usefulness of the long-wavelength ultraviolet light emitted by the Wood's light in the diagnosis of several forms of porphyria. The porphyrias are a group of disorders due to abnormalities in the production of the protoporphyrin part of the heme molecule ( heme = protoporphyrin + iron). In all forms of the disease, excessive amounts of one or more of the various precursors of protoporphyrin or of protoporphyrin itself are produced. In acute intermittent porphyria, which is characterized by neurological complaints, the earliest precursors ( δ-aminolevulinic acid and porphobilinogen) are excreted in the urine. These compounds have not yet become porphyrins and do not fluoresce. The patients are not sensitive to sunlight. All other forms of porphyria are characterized by sun sensitivity and the presence of porphyrin compounds in serum and tissues in elevated amounts. Porphyrins absorb long-wavelength ultraviolet light (4,000 Angstrom) and emit light of a longer
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Hepatic conversion of porphobilinogen to porphyrins was less than 50% of control levels in human subjects with the genetic disease, intermittent acute porphyria. This relative block in heme biosynthesis may be relevant to a concomitant 6- to 10-fold elevation in δ-aminolevulinic acid synthetase activity, since this first and rate-controlling enzyme in the biosynthetic pathway is subject to negative feedback regulation by the end product, heme. A micro-radio-chemical assay of δ-aminolevulinic acid synthetase, and some of its applications, are described.
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Porphobilinogen deaminase
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