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)

Altered hepatic microsomal drug metabolism has been reported to occur in afflicted with hyperbilirubinemia. Similarities of the chemical structures of hydroxymethylbilane, an intermediate in the biosynthesis of uroporphyrinogen, to bilirubin prompted investigations of the effect of bilirubin on the activity of uroporphyrinogen I synthase (porphobilinogen deaminase, EC 4.3.1.8) and the biosynthesis of heme. Bilirubin was found to be a reversible, noncompetitive inhibitor of uroporphyrinogen I synthase. The inhibition constant (Ki) for bilirubin was 1.5 microM. Bile acids had no effect on rat hepatic uroporphyrinogen I synthase activity. Hyperbilirubinemia was achieved in rats by biliary ligation in order to investigate whether elevated levels of bilirubin impair the biosynthesis of hepatic heme in vivo. The relative rate of heme biosynthesis, as measured by the rate of incorporation of delta-[4-14C]aminolevulinic acid into heme, was decreased 59% 24 h after biliary obstruction. The levels of hepatic microsomal heme and cytochrome P-450 were decreased by 43 and 40%, respectively, 72 h after biliary obstruction. The activities of hepatic delta-aminolevulinic acid synthase and uroporphyrinogen I synthase were increased by 39 and 46%, respectively, 72 h after biliary obstruction. During the 48- to 72-h period following biliary obstruction, the urinary excretion of porphobilinogen and uroporphyrin was increased 3.0- and 3.5-fold, respectively, whereas, the urinary excretion of delta-aminolevulinic acid was not altered. During this 48-to 72-h time interval following biliary obstruction, 100% of the uroporphyrin was excreted as isomer I. These results indicate that bilirubin is capable of depressing the biosynthesis of rat hepatic heme and thus cytochrome P-450-mediated drug metabolism by inhibition of the formation of uroporphyrinogen. These findings are a plausible mechanism for reports of impaired clearance of various drugs in patients afflicted with hyperbilirubinemic disease states.
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PMID:Inhibition of the biosynthesis of uroporphyrinogen and heme in rat liver during obstructive jaundice produced by bile duct ligation. 396 18

Unexpected differences in clinical and biochemical findings in two brothers occupationally exposed to the same source of lead for dissimilar lengths of time are presented. Only the brother with the shorter period of lead exposure was anemic and afflicted by nausea, vomiting, abdominal colic and arthralgia. His urinary PBG output yielded the high orders of magnitude found in acute intermittent porphyria in relapse. Prior to administration of a single dose of EDTA (1 g of the calcium disodium salt given intravenously in 325 mL 0.15 mol/L NaCl), his blood lead levels averaged 3.6 mumol/L. The amount of chelatable lead retrieved from his urine, 31 mumol/day, was more than twice that found in his asymptomatic counterpart who was exposed to lead for 13 months and whose pre-EDTA blood lead levels averaged 4.0 mumol/L. Not only the activity of delta-aminolaevulinic acid dehydratase, but also that of uroporphyrinogen I synthetase, was markedly inhibited by lead in red cells of both brothers. These activities were restored to normal levels in vitro by addition to the assay system of zinc and dithiothreitol. This ruled out a coexisting genetic deficiency of either enzyme. The anemia of the symptomatic brother with the shorter period of lead exposure was alleviated by folic acid, 15 mg/day. The differences in findings between the two brothers point to differential susceptibility to lead and illustrate the extent to which symptomatic lead poisoning may mimic biochemical and clinical features of the acute porphyrias.
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PMID:Occupational lead exposure: studies in two brothers showing differential susceptibility to lead. 401 20

The treatment of rats with cis-platinum for 7 days caused a profound, and seemingly selective, decrease (70-80%) in the microsomal cytochrome P-450 levels in the testis. This decrease was accompanied by marked reductions (70-80%) in steroid 17 alpha-hydroxylase activity and in plasma testosterone concentration. The treatment of rats with human chorionic gonadotropin partially restored the cytochrome P-450 concentration and 17 alpha-hydroxylase activity and permitted the plasma testosterone level to approach control values. The effect of cis-platinum on the testicular cytochrome P-450 appeared unrelated to deficiencies in heme metabolic processes, in so far that neither was the activity of delta-aminolevulinate synthetase decreased, nor was that of heme oxygenase increased. These enzymes are rate-limiting in heme biosynthesis and degradation pathways, respectively. Also, the activities of uroporphyrinogen I synthetase, delta-aminolevulinate dehydratase, and ferrochelatase and the concentration of total porphyrins in the testis remained unchanged. The sodium dodecyl sulfate-gel electrophoresis of the microsomal preparation did not reveal a diminished level of apocytochrome; however, in this preparation, heme could not be detected in molecular weight regions corresponding to cytochrome P-450. The microsomal cytochrome b5 and the mitochondrial heme concentrations were not decreased in cis-platinum-treated rats. It is suggested that the mechanism of depletive action of cis-platinum on microsomal cytochrome P-450 involves an impairment of the effective assembly of heme and apoprotein moieties. It is further suggested that the anterior pituitary hormones control the factor(s) involved in this assembly, a process which is interrupted by cis-platinum.
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PMID:Inhibition of testicular cytochrome P-450-dependent steroid biosynthesis by cis-platinum. Reversal by human chorionic gonadotropin. 403 24

We describe a simple spectrophotometric microassay to quantify the proliferation and the differentiation of human bone marrow or blood erythroid progenitor cells CFU-E and BFU-E. These precursors give rise, in culture, to colonies and bursts with markedly variations in size and hemoglobinization, which cannot be accurately evaluated by the usual method of scoring. We then developed a sensitive biochemical microassay to measure the uroporphyrinogen I synthase activity of progenitors grown in small wells. This assay is a valuable index of erythroid differentiation in vitro. This method can offer the opportunity to test the efficiency in vitro of various therapeutic agents in patients with hemopoietic disorders.
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PMID:Uroporphyrinogen I synthase assay as an evaluation of the in vitro development of human BFU-E and CFU-E. 406 65

A new spectrofluorometric assay is described for quantitating uroporphyrinogen I synthase (EC 4.3.1.8) activity in volumes of human blood as small as 2 mul. By this sensitive assay the inheritance of the enzyme's activity has been studied and the genetic defect for acute intermittent porphyria has been confirmed to be autosomal dominant in nature. There is a 3-fold range of uroporphyrinogen I synthase activity in erythrocytes in the normal population, with a mean V(max) +/- SD of 35.7 +/- 8.4 nmol of uroporphyrinogen I formed per ml of erythrocytes per hr, at 37 degrees . One-half this level of enzyme activity (18.0 +/- 5.0) is found in erythrocytes from patients with clinically manifest acute intermittent porphyria; and in erythrocytes from those of their relatives, including prepubertal children, who have the latent gene defect for the disease. The K(m) of erythrocyte enzyme of normal people is 12.3 +/- 3.9 muM, whereas the K(m) of the erythrocyte enzyme of patients with acute intermittent porphyria is 6.2 +/- 3.9 muM, as determined on whole blood lysates. Three enzymic changes have now been identified in patients with acute intermittent porphyria; a high level of delta-aminolevulinate synthase activity; a low level of uroporphyrinogen I synthase activity; and a deficiency of steroid Delta(4)-5alpha reductase activity.
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PMID:A microassay for uroporphyrinogen I synthase, one of three abnormal enzyme activities in acute intermittent porphyria, and its application to the study of the genetics of this disease. 452 87

Porphyria cutanea tarda (PCT) is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I. Clinical evidence has implicated iron in the pathogenesis of PCT. The synthesis of the normally occurring isomer of uroporphyrin, namely uroporphyrin III, from porphobilinogen (PBG) requires two enzymes; uroporphyrinogen I synthetase and uroporphyrinogen III cosynthetase (COSYN). In the absence of COSYN only uroporphyrinogen I is formed. These experiments were designed to study the effect of iron on porphyrin biosynthesis in porcine and human crude liver extracts and to measure COSYN activity in the presence of iron.Mitochondria-free crude liver extracts were prepared in 0.25 m sucrose at pH 7.4 by centrifugation at 37,000 g. Preparations were incubated with either 0.2 mm amino-levulinic acid (ALA) or 0.1 mm PBG. The addition of ferrous ion (either from ferritin iron [4 mug/ml] and cysteine [6.7 mm] or ferrous ammonium sulfate [0.3 mm Fe] and cysteine) significantly increased the rate of uroporphyrin synthesis from either ALA or PBG. The predominant porphyrin synthesized in the presence of ferrous ion was uroporphyrin I whereas coproporphyrin III predominated in its absence. Orthophenanthroline blocked these effects of ferrous ion.To investigate the effect of ferrous ion on COSYN, crude liver extracts were incubated with ferrous ammonium sulfate (0.3 mm Fe) and cysteine (6.7 mm) and the COSYN activity of the incubates was assayed directly. In both porcine and human extracts ferrous ion caused marked inhibition of COSYN activity. Orthophenanthroline blocked the inhibitory effect.Inactivation of COSYN by heating resulted in marked enhancement of porphyrin synthesis from PBG. The sole product was uroporphyrin I.Thus, inactivation of COSYN results in accelerated synthesis of uroporphyrin I. This effect of ferrous ion provides a possible biochemical explanation for the excess production and excretion of uroporphyrin I in patients with PCT and the reversal of this defect by phlebotomy.
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PMID:The role of iron in the pathogenesis of porphyria cutanea tarda. An in vitro model. 464 Sep 47

Uroporphyrin I is found in high concentration in the bones, teeth, blood, soft tissues, and urine of the fox squirrel, Sciurus niger. The concentration of uroporphyrin in fox squirrel spleen is much higher than in liver, kidney or bone marrow, probably because of accumulation from phagocytosed red cells. Bleeding causes a marked increase in the uroporphyrin concentration of red cells and spleen, and a 3-8-fold increase in uroporphyrin excretion. Urinary excretion of delta-aminolevulinic acid and porphobilinogen is not greater in fox squirrels than in nonporphyric gray squirrels. Sciurus carolinensis, used as controls. In all these characteristics, as well as in the previously demonstrated deficiency of the enzyme uroporphyrinogen III cosynthetase in red cells, the physiological porphyria of fox squirrels resembles congenital erythropoietic porphyria, a hereditary disease of man and cattle. For squirrels differ in showing no evidence of cutaneous photosensitivity or hemolytic anemia. Uroporphyrinogen III cosynthetase activity is present in fox squirrel bone marrow at 1/10 its concentration in gray squirrel marrow. The fox squirrel enzyme is much more unstable than the gray squirrel enzyme, which provides a possible explanation for its low activity and for the overproduction of uroporphyrin I. It is unlikely that the deficiency of cosynthetase is due to its inactivation by excessive amounts of uroporphyrinogen I synthetase, because activity of the latter enzyme is the same in blood from fox and gray squirrels.Fox squirrel porphyria provides a convenient model for studies of pathogenesis of human congenital erythropoietic porphyria.
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PMID:Erythropoietic porphyria of the fox squirrel Sciurus niger. 468 90

Intermittent acute porphyria has recently been distinguished biochemically from other genetic hepatic porphyrias by the observation of diminished hepatic uroporphyrinogen I synthetase activity and increased delta-aminolevulinic acid synthetase activity. Since deficient uroporphyrinogen I synthetase may be reflected in nonhepatic tissues, we have assayed this enzyme in red cell hemolysates from nonporphyric subjects and from patients with genetic hepatic porphyria. Only patients with intermittent acute porphyria had decreased erythrocyte uroporphyrinogen I synthetase activity which was approximately 50% of normal. The apparent K(m) of partially purified uroporphyrinogen I synthetase was 6 x 10(-6)m in both nonporphyrics and patients with intermittent acute porphyria. These data provide further evidence for a primary mutation affecting uroporphyrinogen I synthetase in intermittent acute porphyria. Further-more, results of assay of red cell uroporphyrinogen I synthetase activity in a large family with intermittent acute porphyria suggest that this test may be a reliable indicator of the heterozygous state.
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PMID:Decreased red cell uroporphyrinogen I synthetase activity in intermittent acute porphyria. 505 53

A cDNA clone containing sequences complementary to the mRNA coding for anemic rat spleen porphobilinogen deaminase (EC 4.3.1.8) has been isolated. A cDNA library was prepared from partially purified mRNA (1% purity). This library was then screened by colony hybridization, using a cDNA probe derived from porphobilinogen deaminase mRNA further enriched (10-20% purity) by gel electrophoresis in the presence of methylmercury hydroxide. Colonies hybridizing with the probe were analyzed by hybrid-selected translation using anemic rat spleen mRNA. Four recombinant plasmids containing porphobilinogen deaminase cDNA sequences were identified by specific immunoprecipitation of the translational product from hybrid-selected mRNA. Porphobilinogen deaminase mRNA was shown to contain 1800 bases by blot hybridization analysis. The cloned cDNA sequence consists of 1500 bases. Hybridization analysis of poly(A)+ RNA from uninduced and induced mouse erythroleukemic cells indicated that induction to erythroid differentiation by dimethyl sulfoxide results in a 10-fold increase of porphobilinogen deaminase mRNA. The rat cDNA clones hybridize to the corresponding sequences encoding human porphobilinogen deaminase. This property will be useful for isolation of human gene(s) and further characterization of the molecular lesion(s) responsible for acute intermittent porphyria.
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PMID:Molecular cloning of a cDNA sequence complementary to porphobilinogen deaminase mRNA from rat. 608 72

An autopsy case of a 37-year-old woman with acute porphyria is reported. The patient began to complain of severe menstrual pains, and later developed serious peripheral neuropathy and various autonomic nervous symptoms. The autopsy revealed a marked loss and degeneration of axons and myelin sheaths in the peripheral nervous system (PNS), and prominent central chromatolysis of the spinal anterior horn cells. The predominant process of the peripheral neuropathy appeared to be axonal degeneration. Biochemical analysis showed a marked increase of delta-aminolevulinic acid (ALA), porphobilinogen, uroporphyrin, and coproporphyrin in the urine, and an increase of coproporphyrin and protoporphyrin in the stools and blood. In the analysis of the enzymatic activities of the liver and bone narrow, the activity of ALA synthetase (ALA-S) was markedly increased, and the activities of both uroporphyrinogen I synthetase (URO-S) and ferrochelatase were decreased. It was characteristic in this case that the enzymatic abnormalities found in both acute intermittent porphyria (AIP) and variegate porphyria (VP) coexisted. Biochemical analysis of the sciatic nerve showed an increase of ALA-S activity and a decrease of both URO-S and ALA dehydrase activities. This was the first report that indicated the presence of abnormal activities of the heme biosynthetic enzymes in the peripheral nerves of porphyric patients. The possibility was discussed that these enzymatic abnormalities of the heme biosynthesis in the peripheral nerve itself might be strongly related to the pathogenesis of the porphyric neuropathy.
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PMID:An autopsy case of acute porphyria with a decrease of both uroporphyrinogen I synthetase and ferrochelatase activities. 608 95


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