Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three genes hemE, hemF, hemG taking part in the porphyrin biosynthesis of Baccillus subtilis were mapped by two- and three-factor transduction crosses. The gene hemE determines uroporphyrinogen decarboxylase (EC 4.1.1.37) the gene hemF coproporphyrinogen oxidase (EC 1.3.3.3) and the gene hemG ferrochelatase (EC 4.99.1.1) enzymes. The loci hemE, hemF, hemG, are not linked to hemA locus and located near the argC and metD loci.
Mol Gen Genet 1976 Jul 05
PMID:Mapping the uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase loci in Bacillus subtilis. 82 75

1. The activities of six of the enzymes of haem biosynthesis have been assayed in peripheral blood from patients with lead poisoning, acute intermittent porphyria or hereditary coproprophyria. 2. Compared with normal subjects the lead-poisoned subjects had highly significant depression of delta-aminolaevulinate dehydratase, coproporphyrinogen oxidase and ferrochelatase. 3. Lead-poisoned subjects had highly significant elevation of delta-aminolaevulinate synthase activity. 4. delta-Aminolaevulinate synthase activity was inversely related to the haemoglobin concentration. 5. Increased delta-aminolaevulinate synthase and decreased delta-aminolaevulinate dehydratase activity are also found in acute intermittent porphyria. 6. Increased delta-aminolaevulinate synthase, normal prophobilinogen deaminase and uroporphyrinogen decarboxylase and decreased coproporphyrinogen oxidase are found in both lead poisoning and hereditary coproporphyria. 7. These enzyme changes explain the recognized patterns of porphyrins and prophyrin precurosrs in blood and urine in these conditions.
Clin Sci Mol Med 1977 Oct
PMID:Alterations in the activity of enzymes of haem biosynthesis in lead poisoning and acute hepatic prophyria. 91 57

1. The activities of the enzymes of haem biosynthesis were studied in 23 patients with acute intermittent porphyria. The mitochondrial enzymes delta-aminolaevulinate synthase, coproporphyrinogen oxidase and ferrochelatase were measured in leucocytes and the cytosolic enzymes delta-aminolaevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase in erythrocytes. 2. Leucocyte delta-aminolaevulinate synthase activity was elevated (P less than 0-001), with marked diminution of porphobilinogen deaminase activity (P less than 0-001) and reduction in the activities of delta-aminolaevulinate dehydratase (P less than 0-01) and uroporphyrinogen decarboxylase (P less than 0-005). 3. A therapeutic regimen based on intravenous laevulose infusion was studied. In four patients in acute attack and one in remission laevulose treatment was associated with a fall in delta-aminolaevulinate synthase activity, a rise in porphobilinogen deaminase and uroporphyrinogen decarboxylase activities, and a fall in urinary prophyrin precursor excretion (P less than 0-001). These studies provide a basis for the evaluation of the use of sugars in acute intermittent porphyria.
Clin Sci Mol Med 1977 10
PMID:The treatment of acute intermittent porphyria with laevulose. 91 61

1. There is no known cause for the increased mortality due to ischaemic heart disease in soft water areas. Since the lead concentration of soft water is elevated in houses with lead plumbing, studies have been carried out to determine the effects of lead on the heart of rats. 2. Rats were given drinking water containing lead for 1 year at concentrations similar to those found previously in Glasgow, which has a soft water supply. 3. There was increasing deposition of lead in the heart and a fall in the cardiac levels of the enzymes ferrochelatase and delta-aminolaevulinic acid dehydratase. These changes are maximal after 6 months, when there were marked electron-microscopic changes in the myocardium and myocardial mitochondria. 4. Further studies are needed to determine whether lead is a cause of the increased mortality from ischaemic heart disease in soft water areas.
Clin Sci Mol Med 1975 Oct
PMID:Cardiac effects of lead in drinking water of rats. 119 93

N-Ethylprotoporphyrin (N-ethyl-PP) was isolated from the livers of phenobarbital-pretreated rats after the administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine, separated into its four regioisomers by high performance liquid chromatography, and quantitated. The percentage ratio, in the chromatogram, of the peak areas of the ring A-substituted (NA) and the ring B-substituted (NB) regioisomers was 80:20, compared with 50:50 for synthetic N-ethyl-PP. The NA regioisomer of N-ethyl-PP isolated from rat liver was found to be approximately 5 times more potent an inhibitor of ferrochelatase than was the NB regioisomer. Because the synthetic NA regioisomer (an equal mixture of the NA and the epi-NA enantiomers) is equipotent with the synthetic NB regioisomer (an equal mixture of the NB and the epi-NB enantiomers), epi-NB must be more potent than epi-NA. The higher potency previously observed with the NA plus NB regioisomers of N-ethyl-PP isolated from rat liver, compared with the NA plus NB regioisomers of synthetic N-ethyl-PP, is explained by the fact that the biological preparation contains 80% of the potent NA, compared with 25% of the potent NA and 25% of the potent epi-NB in the synthetic preparation. The critical features for optimal ferrochelatase-inhibitory activity are the ring A N-ethyl group facing downward in the NA isomer and the ring B N-ethyl group in the epi-NB isomer being rotated through 180 degrees to occupy the same position. According to one proposed mechanism, N-alkylprotoporphyrins inhibit ferrochelatase by serving as transition state analogues for the iron insertion step. X-ray crystallography shows that the N-alkyl group-bearing pyrrole ring and the pyrrole ring opposite to the N-alkyl group are tilted out of planarity in opposite directions. We suggest that this tilting reflects the normal conformational changes required for the insertion of iron into the protoporphyrin IX ring by ferrochelatase and that the greater inhibitory activity of NA and epi-NB isomers, compared with epi-NA and NB isomers, is due to the fact that the normal mechanism for ferrochelatase-catalyzed iron insertion has preference for an A-C ring tilt over a B-D ring tilt.
Mol Pharmacol 1992 Aug
PMID:Evidence for the stereoselective inhibition of chick embryo hepatic ferrochelatase by N-alkylated porphyrins. II. 151 28

Six mutants of Escherichia coli K12 that are sensitive to visible light have been isolated. Five of them, including an amber mutant, are defective in a gene that maps near 11 minutes on the linkage map of the chromosome, and this gene has been designated visA. The sixth mutant, which was isolated from bacteria that carried the visA+/visA+ diploid allele, is defective in a gene that maps near 63 minutes on the linkage map, which has been designated visB. These mutant strains of bacteria are killed by illumination with visible light. The effective wavelength of the light is around 460 nm. The nucleotide sequence of the visA gene was determined. As a result of a search for homologous products, we found that visA may be identical to hemH, the structural gene for ferrochelatase which catalyzes a final step in the biosynthesis of heme. A possible mechanism for the killing of the visA mutant bacteria is discussed.
J Mol Biol 1991 Jun 05
PMID:Isolation and characterization of visible light-sensitive mutants of Escherichia coli K12. 205 80

3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and its 4-propyl analogue were administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPPs) that were isolated from rat livers, viz., N-ethylPP and N-propylPP, were found to have greater ferrochelatase-inhibitory potency than the corresponding synthetic N-alkylPPs. The N-ethylPP that was isolated from rat liver was found to contain 72% of the NB plus NA regioisomers, whereas synthetic N-ethylPP contained 40% of the NB plus NA regioisomers. In contrast, the N-propylPP that was isolated from rat liver contained the same amount of the NB/A regioisomer(s) as synthetic N-propylPP (33%). The NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver were found to be significantly more potent than the corresponding synthetic regioisomers. We conclude that 1) the ferrochelatase-inhibitory potency of N-ethylPP that is isolated from rat liver is greater than that of synthetic N-ethylPP, due to differences in both regioisomer composition and the inhibitory potency of the NB plus NA regioisomers and stereoisomers, and 2) the ferrochelatase-inhibitory potency of N-propylPP that is isolated from rat liver is greater than that of synthetic N-propylPP, due solely to the difference in the ferrochelatase-inhibitory potency of the NB/A regioisomer(s) and stereoisomers. From the enhanced ferrochelatase-inhibitory potency of the NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver, relative to the corresponding synthetic N-alkyllPP regioisomers, it was inferred that 2- and 4-vinyl substituents located on pyrrole rings A and B contribute to the optimal binding of N-alkylPPs to the ferrochelatase active site.
Mol Pharmacol 1989 Oct
PMID:Evidence for the stereoselective inhibition of chick embryo hepatic ferrochelatase by N-alkylated porphyrins. 281 58

A series of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), viz. 4-butyl DDC, 4-pentyl DDC, and 4-hexyl DDC was administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPP) isolated from the rat livers were separated into regioisomers by means of high performance liquid chromatography; the NB or NA (NB/A) regioisomers constituted 19-26% of the total regioisomers. Considerable ferrochelatase-inhibitory activity was found in the NB/A regioisomers; the NC or ND (NC/D) regioisomers had little ferrochelatase-inhibitory activity. These findings supported the idea that the ferrochelatase active site could accommodate alkyl groups larger than methyl only if they were present on the nitrogens of the A or B pyrrole rings of the N-alkylPP. The inactivity of 4-isobutyl DDC as a ferrochelatase-lowering agent was investigated. After injection of 4-isobutyl-DDC into phenobarbital-pretreated rats, N-isobutylPP was isolated from the rat livers and separated into its regioisomers; the NB/A regioisomer constituted 3.8% of the total regioisomers. The NB/A regioisomer was found to have appreciable ferrochelatase-inhibitory activity whereas the NC/D regioisomer was inactive. The inactivity of 4-isobutyl-DDC as a ferrochelatase-lowering agent was attributed to the small amount of NB/A regioisomer present in the N-isobutylPP regioisomer mixture.
Mol Pharmacol 1988 Jul
PMID:Differential inhibition of hepatic ferrochelatase by regioisomers of N-butyl-, N-pentyl-, N-hexyl-, and N-isobutylprotoporphyrin IX. 339 43

The ferrochelatase-inhibitory activity, porphyrin-inducing activity, and cytochrome P-450- and heme-destructive effects of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. The ferrochelatase-inhibitory activity of the 4-butyl, 4-pentyl, 4-hexyl, and 4-cyclopropylmethyl analogues of DDC was considered to be due to the formation of the corresponding N-alkylporphyrins. These N-alkylporphyrins were isolated from the livers of phenobarbital-pretreated rats following administration of the corresponding DDC analogues. The 4-isobutyl analogue did not have ferrochelatase-inhibitory activity despite its ability to cause formation of an N-isobutylporphyrin in rat liver. The 4-chloromethyl analogue of DDC inhibited ferrochelatase activity. The inability to isolate an N-alkylporphyrin from rat liver with this analogue may be due to its lability. The porphyrin-inducing activity of these analogues depended on their ferrochelatase-inhibitory potency and lipophilicity. The DDC analogues caused cytochrome P-450 and heme destruction. The relative ferrochelatase-inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site.
Mol Pharmacol 1986 Oct
PMID:Ferrochelatase-inhibitory activity and N-alkylprotoporphyrin formation with analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) containing extended 4-alkyl groups: implications for the active site of ferrochelatase. 376 22

The ferrochelatase-reducing activity and cytochrome P-450- and heme-destructive effects of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. A group of DDC analogues was found in which an inability to reduce ferrochelatase activity corresponded with an inability to cause cytochrome P-450 and heme destruction. In a second group of DDC analogues, the ability to reduce ferrochelatase activity corresponded with the ability to cause cytochrome P-450 and heme destruction. These observations support the idea that the protoporphyrin IX moiety of N-alkylprotoporphyrin IX originates from the heme moiety of cytochrome P-450. A third group of DDC analogues caused cytochrome P-450 and heme destruction despite an inability to reduce ferrochelatase activity. With this third group of DDC analogues, the heme moiety of cytochrome P-450 is likely degraded to products other than N-alkylporphyrins. The inability of several lipophilic DDC analogues [4-benzyl, 4-isopropyl, 4-cyclohexyl, 4-(3-cyclohexenyl)] to reduce hepatic ferrochelatase activity may explain their low porphyrinogenicity. The pattern of porphyrin accumulation produced in response to two DDC analogues that did not inhibit ferrochelatase was investigated using high performance liquid chromatography. Coproporphyrin was the major porphyrin to accumulate in response to the 4-isopropyl analogue and uro- and heptacarboxylic acid porphyrins in response to the 4-benzyl analogue. These patterns of porphyrin accumulation are consistent with the inability of these analogues to inhibit ferrochelatase.
Mol Pharmacol 1985 Apr
PMID:Suicidal destruction of cytochrome P-450 and reduction of ferrochelatase activity by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine and its analogues in chick embryo liver cells. 398 91


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