Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme biosynthetic activity in the symbiotic association involving crithidial flagellates and intracellular bacteroids was studied by enzymic, nutritional, and isotope incorporation experiments. Component organisms and their complexes in this association were analyzed separately to determine the underlying cause of the hemin requirement of hemoflagellates and the role of symbiotes in sparing this requirement of two crithidial species. Nutritional study of symbiote-free flagellates showed that their growth requires at least 0.1 mug/ml of hemin, which can be substituted by protoporphyrin IX, but not by the porphyrin precursors, delta-amino-levulinic acid or porphobilinogen. These flagellates, in the presence of protoporphyrin IX, incorporated 59Fe into heme, indicating that they possess ferrochelatase (EC 4.99.1.1), the terminal enzyme in the heme biosynthetic pathway, which catalyzes the insertion of iron into protoporphyrin IX. In symbiote-containing flagellates serially cultured in a defined medium free of tetrapyrrole compounds, heme and porphyrins can be detected by a fluorophotometric method, indicative of heme biosynthesis. Study of [14C]glycine incorporation into heme showed that the rate is much higher in symbiote-containing flagellates than in those without symbiotes. Microassay of uroporphyrinogen I synthase [EC 4.3.1.8; porphobilinogen ammonia-lyase (polymerizing)] revealed that the specific activity is high in symbiote-containing flagellates and higher still in isolated symbiotes, but essentially negligible in symbiote-free organisms. It is concluded that the bacterial symbiotes augment a very limited heme biosynthetic capacity of host flagellates by supplying uroporphyrinogen I synthase and perhaps other enzymes preceding ferrochelatase in the heme biosynthetic chain.
 ...
PMID:Heme biosynthesis in bacterium-protozoon symbioses: enzymic defects in host hemoflagellates and complemental role of their intracellular symbiotes. 81 Jul 95

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.
 ...
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.
 ...
PMID:Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver. 90

A simple spectrophotometric method for uroporphyrinogen I synthetase in erythrocytes is described. Results obtained on intermittent acute porphyria patients and carriers are similar to the results obtained with fluorimetric methods. Reproducibility, relationship between enzyme activity and enzyme concentration, and effect of time on enzymatic activity are described.
 ...
PMID:The spectrophotometric determination of uroporphyrinogen I synthetase activity. 94 11

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.
 ...
PMID:Erythrocyte uroporphyrinogen I synthase activity in diagnosis of acute intermittent porphyria. 97 42

The hereditary hepatic porphyrias are disorders of porphyrin and haem synthesis characterized by a marked idiosyncrasy towards a variety of lipid soluble drugs. Most of these agents are inducers of the haemoprotein cytochrome P450, the terminal oxidase in drug metabolism. The primary genetic defect in intermittent acute porphyria is a partial deficiency of uroporphyrinogen I synthetase, which may result in a secondary derepression of delta-aminoaevulinic acid synthetase, the rate-limiting enzyme in the haem pathway. Analogous defects at more distant sites may explain the other hereditary hepatic porphyrias. As drug sensitivity may be related to the defect in haem synthesis, we investigated the effects of experimental partial blocks in haem synthesis produced by lead in rats. Drug effects on delta-aminolaevulinic acid synthetase, cytochrome P450, And drug metabolism were studied. Our findings indicate: a) While partial impairment of haem biosynthesis has only minor effects on delta-aminolaevulinic acid synthetase activity, it greatly enhances the sensitivity of delta-aminolaevulinic acid synthetase to induction by drugs and steroids, which when given alone, have little or no inducing effect on the enzyme. b) The experimental partial block in haem synthesis delays and impairs drug-mediated induction cytochrome P450 and drug metabolism in vitro. The findings may explain why a large number of structurally unrelated compounds with little effect on normal liver can precipitate "aucte porphyria".
 ...
PMID:Effect of lead on hepatic delta-aminolaevulinic acid synthetase activity in the rat: a model for drug sensitivity in intermittent acute porphyria. 97 99

We describe a spot test for detecting deficiency of uroporphyrinogen I synthase (EC 4.3.1.8), which is characteristic of intermittent acute porphyria. The specimens used for enzyme assay are 6.5-mm filter paper discs saturated with dried blood (less than 15 mul) that was collected by direct application from a fingerstick or from venipuncture, with or without anticoagulant. The enzyme in such specimens is stable for at least nine days at -20 or c degrees C or for two days at room temperature. 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. Trichloroacetic acid is added and, after centrifugation, the supernate is examined visually with a long-wavelength ultraviolet lamp. Samples from normal and porphyric subjects are readily differentiated, both by color and intensity of the resulting porphyrin fluorescence. Anemia is a potential source of falsely positive tests, but one may accurately determine the concentration of hemoglobin in the whole blood on the filter paper discs. Moreover, the fluorescence of normal but anemic samples clearly differs qualitatively from that of porphyric specimens. Another source of falsely positive tests, variation in enzyme activity creating an overlap zone of normal and porphyric results, has not been a confounding problem. The method thus seems to offer promise for screening populations for this disorder.
 ...
PMID:A spot test for uroporphyrinogen I synthase, the enzyme that is deficient in intermittent acute porphyria. 100 Jul 96

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.
 ...
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.
 ...
PMID:Porphyrin synthesis and mitochondrial respiration in acute intermittent porphyria: studies using cultured human fibroblasts. 114 34

Measurement of uroporphyrinogen I synthetase activity in red blood cells indicates a 40-50 p.cent decrease in patients with intermittent acute porphyria (30 +/- 6 units) when compared to normal control subjects (50 +/- 8 units). This measurement makes relatively easy the detection of asymptomatic carriers of the genetic defect, as early as the first day of life.
 ...
PMID:[Acute intermittent porphyria. Detection of asymptomatic carriers of the genetic defect]. 116 81


<< Previous 1 2 3 4 5 6 7 8 9 Next >>