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 activities of the enzymes of heme biosynthesis (except protoporphyrin oxidase) have been followed during the induction of Friend cells in culture. All the enzyme activities increased after induction with dimethyl sulfoxide. The activities of the intermediate enzymes were much higher than those of delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37], the initial enzyme, or ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1), the final enzyme of the pathway. Ferrochelatase activity was not detectable in the uninduced cell. delta-Aminolevulinate synthase activity increased during the first 24 hr of induction; porphobilinogen deaminase activity began to increase after 48 hr and ferrochelatase activity, after 72 hr. However, the induction of heme synthesis followed the same time course as that of ferrochelatase activity, not that of delta-aminolevulinate synthase activity. The cellular growth medium was found to contain traces of protoporphyrins. Thus, ferrochelatase is shown to be rate limiting for heme synthesis during early stages of Friend cell induction. A Friend cell variant (Fw), which is not inducible except in the presence of exogenous hemin, was also studied. All the enzymes of heme synthesis except ferrochelatase were inducible by butyric acid. Ferrochelatase was not inducible by butyric acid or hemin plus butyric acid. These cells also excrete protoporphyrin, The failure to induce ferrochelatase activity is believed to be the cause of, not a consequence of, the noninducibility of this cell line.
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PMID:Heme biosynthesis in Friend erythroleukemia cells: control by ferrochelatase. 28 6

In two young patients with acute hepatic porphyria syndrome and persisting paralyses, which increased in intensity during intermittent occurring crisis, the activity of erythrocyte porphobilinogen synthase (delta-aminolevulinic acid dehydratase) was found to be considerably diminished, below 1% of the value of normal control persons. In contrast, the activity of uroporphyrinogen synthase was normal. Both patients have been excreting high quantities of delta-aminolevulinic acid and porphyrins in urine for years. Lead intoxication has definitively been excluded. Since the relatives also show lower activities in porphobilinogen synthase, the disease of these two patients is probably a new enzymatic type of inherited acute hepatic porphyria, the excretion profile of which is qualitatively completely different from those of the known acute porphyrias. The discovery of this porphyria confirms the theory of overlapping transition in the biochemical and clinical symptoms and analogies among acute hepatic porphyrias.
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PMID:New type of hepatic porphyria with porphobilinogen synthase defect and intermittent acute clinical manifestation. 51 4

Assay of erythrocyte uroporphyrinogen I synthase is an accepted diagnostic test for acute intermittent porphyria, particularly in those individuals who are asymptomatic or in whom the disease is not biochemically manifested by excretion of excess porphyrin precursor. The assay described is based upon a coupled-enzyme procedure in which added delta-aminolevulinic acid and its dehydratase present in erythrocytes are used to generate porphobilinogen as substrate for uroporphyrinogen synthase. Zinc and dithiothreitol are added with preincubation to give maximum activity and reproducibility. These agents also prevent inhibition by lead. Healthy young women had a mean activity of 40 nmol of porphyrin formed per milliliter of erythrocytes per hour, men and activity of 38 nmol/ml/h. Preparation of control specimens is described. This assay gave within-day CVs ranging from 1.9 to 2.8%. Precautions in interpretation of results are discussed.
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PMID:Modified erythrocyte uroporphyrinogen I synthase assay, and its clinical interpretation. 69 83

Porphyrin biosynthesis in mammalian skin and in skin obtained from patients with selected types of porphyria has been studied. Cutaneous porphyrinogenesis required the precursor delta-aminolevulinic acid (ALA) which, when added to murine, rat, and human skin in vitro, was rapidly converted to porphyrins. Total porphyrin content was quantitated by fluorescence assay, and spectral studies indicated that more than 80% of the porphyrin produced was protoporphyrin. The majority of skin porphyrinogenesis occurrred in epidermis or in epidermal derivatives such as hair roots. Known inducers of hepatic delta-aminolevulinic acid synthetase (ALAS), the rate-limiting enzyme for heme biosynthesis, were not inducers when added to skin in vitro. Skin from patients with acute intermittent porphyria demonstrated a 43% decrease in cutaneous porphyrin production as compared to unaffected normals. This is consistent with the known deficiency of uroporphyrinogen synthetase that has been previously demonstrated in the liver and red blood cells of these patients. Porphyrinogenesis in skin of patients with porphyria cutanea tarda was not different from controls. These studies demonstrate that skin has the enzymatic capacity to synthesize porphyrins from added ALA and that cutaneous porphyrinogenesis from ALA is deficient in patients with acute intermittent porphyria.
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PMID:Studies in porphyria. VI. Biosynthesis of porphyrins in mammalian skin and in the skin of porphyric patients. 83 Jul 70

These studies demonstrate altered activities of renal heme biosynthetic pathway enzymes and elevated levels of urinary uroporphyrin and coproporphyrin in rats during chronic exposure to 3, 5, or 10 ppm methyl mercury hydroxide (MMH). Porphyrinuria appears to occur as a result of inhibition of renal ferrochelatase and uroporphyrinogen I synthetase, with secondary induction of delta-aminolevulinic acid (ALA) synthetase in kidneys but not livers of mercury-exposed rats. Since the renal heme biosynthetic system appears to be highly sensitive to MMH during continuous exposure to levels below those which elicit overt general organ damage, these results may have clinical utility in diagnosing pre-toxic biological responses to mercury in human populations.
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PMID:Renal porphyrinuria during chronic methyl mercury exposure. 88 12

In these studies the effects of ingested arsenic (As(+5)) on hepatic heme biosynthetic capability and hemoprotein function in adult male rats were investigated. Animals exposed for 6 weeks to 0, 20, 40, or 85 ppm sodium arsenate in the drinking water suffered depression of hepatic delta-aminolevulinic acid (ALA) synthetase and heme synthetase (ferrochelatase) activities, with maximal decreases to 67 and 55% of control levels, respectively, at 85 ppm. Concomitantly, urinary uroporphyrin levels were elevated by as much as 12 times, and coproporphyrin by as much as 9 times, control values. The rate of incorporation of (3)H-ALA into mitochondrial and microsomal hemes was depressed by 40-50% at 20 ppm but was increased with regard to controls by as much as 150% at the higher treatment levels. A similar biphasic pattern was observed in regard to (14)C-leucine incorporation into cellular membranal proteins. In contrast, the levels of ALA dehydratase, uroporphyrinogen I synthetase, aminopyrine demethylase, and cytochrome P-450 were not significantly changed in As(+5)-treated rats. These results support the hypothesis that chronic, low level, arsenic exposure results in selective inhibition of mitochondrial-bound heme biosynthetic pathway enzymes (ALA synthetase and heme synthetase) resulting in a substantial increase in urinary porphyrins, uniquely characterized by a greater increase in uroporphyrin than coproporphyrin levels. These changes occur independent of, or prior to, alterations in hepatic hemoprotein-dependent functions and may thus serve in the clinical analysis of pretoxic exposure to arsenic compounds in human populations.
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PMID:Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver. 90

Measurement of the activity of uroporphyrinogen I synthase provides an excellent laboratory aid in the diagnosis of acute intermittent porphyria, particularly in those patients who are asymptomatic or in whom the disease is not biochemically manifested by porphyrin precursor excretion. We describe here a simplified fluorometric method for measuring the activity of this enzyme in whole blood. The assay is based upon a coupled-enzyme procedure in which added delta-aminolevulinic acid and the dehydratase that is present in erythrocytes are used to generate porphobilinogen as substrate for uroporphyrinogen synthase. After appropriate incubation the protein is removed we sensitivity, specificity, and precision of the assay compare well with previously described procedures. Activity in nonporphyric male subjects was 31 (SD, 6.0) nmol of porphyrin formed per milliliter of erythrocytes per hour at 37 degrees C. Application of the method for identifying gene carriers of acute intermittent porphyria is demonstrated in three generations of an affected family.
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PMID:Erythrocyte uroporphyrinogen I synthase activity in diagnosis of acute intermittent porphyria. 97 42

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. The disease is complex, involving variable patterns of autonomic and peripheral neuropathy as well as the central nervous system manifestations. There may be alterations in carbohydrate, lipid, water, and electrolyte metabolism in addition to clinically inapparent endocrine abnormalities. The fundamental defect is thought to be a 50% decrease of uroporphyrinogen I synthetase, the third enzyme of the heme biosynthetic pathway. This is associated with a marked increase of hepatic delta-aminolevulinic acid synthetase, the first and rate controlling enzyme of the pathway. The measurement of uroporphyrinogen I synthetase in erythrocytes now provides an enzyme diagnostic test for the disease. Two therapeutic approaches that may prove to reverse the fundamental disease process, at least in some patients, involve [1] a high carbohydrate intake, and [2] intravenous administration of hematin. The latter, only recently introduced, is now being investigated.
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PMID:Acute intermittent porphyria: clinical and selected research aspects. 110 84

The formation of variation of delta-aminolevulinic acid (ALA) and of porphyrins, as well as respiratory metabolism, have been studied in skin fibroblasts from six normal control subjects and seven patients with acute intermittent porphyria. The mean activity of ALA synthetase was the same in both groups, whereas the mean activity of uroporphyrinogen I synthetase (as measured by the conversion of porphobilinogen [PBG] to porphyrins) was significantly decreased in fibroblasts from porphyric subjects, the mean value being 52 per cent that of control subjects (p less than or equal to 0.001). The findings of decreased uroporphyrinogen synthesis without an increase in ALA synthetase in mitochondria-containing cells from subjects with acute intermittent porphyria are compatible with the concept that defective PBG ultilization is the fundamental defect in heme biosynthesis in this disease and the possibility that ALA synthetase is "irreversibly" repressed in nonhepatic tissues. Respiration of the cells was studied polarographically. The two types of cells showed similar overall rates of respiration and in general responded to substrates and inhibitors as expected. Of the inhibitors tested (rotenone, amytal, antimycin, and cyanide), only rotenone showed a differential effect: respiration of fibroblasts from porphyric patients was not as sensitive to the inhibitor as was that of the control subjects. These results are interpreted as suggesting a possible defect in mitochondrial NADH oxidation in acute intermittent porphyria.
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PMID:Porphyrin synthesis and mitochondrial respiration in acute intermittent porphyria: studies using cultured human fibroblasts. 114 34

The green sulfur bacterium, Chlorobium vibrioforme, synthesizes the tetrapyrrole precursor, delta-aminolevulinic acid (ALA), from glutamate via the RNA-dependent five-carbon pathway. A 1.9-kb clone of genomic DNA from C. vibrioforme that is capable of transforming a glutamyl-tRNA reductase-deficient, ALA-dependent, hemA mutant of Escherichia coli to prototrophy was sequenced. The transforming C. vibrioforme DNA has significant sequence similarity to the E. coli, Salmonella typhimurium, and Bacillus subtilis hemA genes and contains a 1245 base open reading frame that encodes a 415 amino acid polypeptide with a calculated molecular weight of 46174. This polypeptide has over 28% amino acid identity with the polypeptides deduced from the nucleic acid sequences of the E. coli, S. typhimurium, and B. subtilis hemA genes. No sequence similarity was detected, at either the nucleic acid or the peptide level, with the Rhodobacter capsulatus or Bradyrhizobium japonicum hemA genes, which encode ALA synthase, or with the S. typhimurium hemL gene, which encodes glutamate-1-semialdehyde aminotransferase. These results establish that hemA encodes glutamyl-tRNA reductase in species that use the five-carbon ALA biosynthetic pathway. A second region of the cloned DNA, located downstream from the hemA gene, has significant sequence similarity to the E. coli and B. subtilis hemC genes. This region contains a potential open reading frame that encodes a polypeptide that has high sequence identity to the deduced E. coli and B. subtilis HemC peptides. hemC encodes the tetrapyrrole biosynthetic enzyme, porphobilinogen deaminase, in these species.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure and expression of the Chlorobium vibrioforme hemA gene. 179 35


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