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)

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. Urinary 17-oxosteroid conjugates were measured by gas-liquid chromatography in five patients with hereditary coproporphyria. 2. Three patients were in an acute attack and showed significantly increased excretion of sulphate or glucuronide conjugates of aetiocholanolone. There was increased excretion of several other related steroids but no consistent pattern was apparent. 3. In the two patients in remission, excretion of urinary 17-oxosteroids was not increased. 4. The ratio of total urinary aetiocholanolone to androsterone (5beta:5alpha) was found to be significantly elevated for the three patients in an acute attack. Serial measurements were made in two of these patients and showed a highly significant linear correaltion between this ratio and the urinary content of delta-aminolaevulic acid and porphobilinogen. 5. These observations suggest the involvement of the 17-oxosteroids, espically aetiocholanolone, in the pathogenesis of hereditary coproporphyria.
Clin Sci Mol Med 1975 Nov
PMID:Urinary excretion of 17-oxosteroids in hereditary coproporphyria. 119 2

Porphyrins and activities of heme biosynthetic enzymes in Taenia solium cysticerci from porcine and human hosts, were examined in order to clarify the possible step where heme synthesis is interrupted. Porphyrins in the vesicular fluid of the parasite were predominantly coproporphyrin, followed by penta-carboxylated porphyrin, which together accounted for 90% of the accumulated porphyrins. Coproporphyrin and penta-carboxylated porphyrin were both type I and III isomers. Small amounts of protoporphyrin and uroporphyrin, and trace amounts of tri-, hexa- and hepta-carboxylated porphyrins were also detected. Fluorescence and phosphorescence spectra and lifetime studies revealed that at least 75% of the porphyrins were bound to metal, probably Zn, while the rest was free. Reverse phase high performance liquid chromatography monitored at an excitation wavelength of 417 nm and at an emission wavelength of 585 nm demonstrated that approximately 90% of these porphyrins were Zn-coproporphyrin. A fluorescence excitation peak at 283 nm with an emission peak at 585 nm and 625 nm indicated that some of the porphyrins were associated with proteins in the vesicular fluid of the parasite. Low levels of delta-aminolevulinic acid dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase activities, and heme concentrations were found in the extract of the parasite walls and scolex, but not in the vesicular fluid. The porphyrin accumulation pattern in this parasite can best be explained by postulating a deficiency of coproporphyrinogen oxidase activity, similar to that in human patients with hereditary coproporphyria. A parasite dissected from a human host was considerably less porphyric than those from pigs, but the pattern of accumulated porphyrins was quite similar in both. In view of their porphyrin contents, T. solium cysticerci could be light sensitive.
Mol Biochem Parasitol 1987 Jan 15
PMID:Analysis of porphyrins and enzymes in porphyrin synthesis in Taenia solium cysticercus from man and pig. 357 46

Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E. coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed.
Hum Mol Genet 1995 Feb
PMID:A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. 775 79

Genomic clones containing a human coproporphyrinogen oxidase gene, were isolated. DNA sequencing indicates that the human CPX gene spans about 14 kb and consists of seven exons and six introns. Sequences were determined for all the exons, exon-intron junctions and for 800 bp of promoter region. Introns vary in size from 269 bp to 5 kb and they all have consensus sequences at their boundaries. Primer extension and ribonuclease protection experiments revealed multiple transcriptional initiation sites in a region with sequence motifs characteristic of a promoter. The promoter region is GC-rich and contains multiple potential Sp 1 elements, CACCC boxes and potential GATA-1 binding sites. The availability of the CPX genomic sequence allowed us to determine the mutation in a patient with a hereditary coproporphyria. AG to A mutation was found at the last position of exon 6. This mutation results in exon skipping.
Hum Mol Genet 1994 Aug
PMID:Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping. 798 9

Coproporphyrinogen oxidase is a mitochondrial heme-biosynthetic enzyme that converts coproporphyrinogen to protoporphyrinogen. Inherited deficiency of this enzyme causes the human genetic disease hereditary coproporphyria. Recently, we isolated, sequenced and expressed the cDNA encoding human coproporphyrinogen oxidase. This allowed us to investigate the nature of the defect leading to a profound deficiency of coproporphyrinogen oxidase in a patient with homozygous hereditary coproporphyria. Using reverse-transcription, amplification of the cDNA and direct sequencing of the amplified products, we found a point mutation resulted in an arginine to tryptophane substitution (R231W). Expression studies of normal and mutated cDNAs in a bacterial system demonstrated that this substitution resulted in the synthesis of an unstable protein with a residual catalytic activity. This is the first mutation to be found at the coproporphyrinogen oxidase locus. Furthermore, three common polymorphisms within the coproporphyrinogen oxidase gene were detected. Two DNA polymorphisms resulted in amino acids changes (H172N and V194I) and the third one was silent (E230E).
Hum Mol Genet 1994 Mar
PMID:Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. 801 60

Rat hepatic coproporphyrinogen oxidase, the sixth enzyme in the heme biosynthetic pathway, was purified 1340-fold with a yield of 39.7%. To obtain the soluble enzyme, different methods were applied to disrupt mitochondria, with sonication giving the highest yield (85%). The minimum catalytic form of enzyme was a dimer with a molecular mass of 77 +/- 4 kDa. The existence of aggregated forms was possible since in fractions of gel filtration elution activity was observed with higher molecular mass. We determined a Stokes radius of 36.3 A, a sedimentation coefficient (S20,w) of 5.06 S, and frictional ratio of 1.29, suggesting a nearly globular shape of the protein. Regardless of the type of salt, high ionic strength inhibits the enzyme, probably modifying its native structure. Experiments with amino acid modifiers showed that histidine, arginine, and tryptophan are involved in the catalytic process. Non-ionic detergents and phospholipids activated the enzyme, probably because they reproduce its natural hydrophobic environment. The present study describes a simple method for the purification of rat liver coproporphyrinogen oxidase, introducing for the first time data on the structure and function of the protein in a tissue often used as a laboratory model in biological studies, and contributing to the study of human hereditary coproporphyria.
Comp Biochem Physiol B Biochem Mol Biol 2000 Oct
PMID:Function and structure of rat hepatic coproporphyrinogen oxidase. 1107 69

A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Molecular, immunological, enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary coproporphyria. 1192 47

The porphyrias are disorders associated with inherited or acquired enzyme deficiencies in the heme biosynthetic pathway. The differential diagnosis is often difficult since the phenotype is very similar in some forms and the biochemical tests are not commonly available. Here we provide an update on the molecular diagnosis of porphyrias in Italy and a flow-chart to facilitate the identification of mutations in heme biosynthetic genes. The molecular analysis has allowed us to identify the molecular defect underlying the disease in 66 probands with different porphyrias [acute intermittent porphyria (AIP), variegate porphyria (VP), porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP)]. No Italian patients with defects in coproporphyrinogen oxidise (CPOX) gene, responsible for hereditary coproporphyria (HCP), have been detected. The molecular characterization has been extended to 115 relatives with the identification of 55 asymptomatic mutation carriers and 60 normal subjects. We have so far identified 50 different mutations among 4 genes associated with the most common porphyrias showing a high molecular heterogeneity: 22 in the hydroxymethylbilane synthase (HMBS) gene (AIP), 7 in the protoporphyrinogen oxidase (PPOX) gene (VP), 16 in the uroporphyrinogen decarboxylase (UROD) gene (PCT) and 5 in the ferrochelatase (FECH) gene (EPP). Among the 50 molecular defects, 29 seem to be restricted to the Italian population.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Molecular characterization of porphyrias in Italy: a diagnostic flow-chart. 1269 45

We report a biochemical and genetic characterization of four cases of hereditary coproporphyria (HCP) in Spain. All patients showed a typical HCP porphyrin excretion pattern with a high concentration of coproporphyrins in feces and inverted I:III isomer ratio. The porphyrin precursors in urine were found elevated in two patients who showed acute symptoms. The analysis of the CPO gene showed that three cases harboured novel mutations: V135A (404T>C; exon 1); L214R (641T>G; exon 2); and P249R (746C>G; exon 3) and in the fourth, a previously described R426X mutation in exon 6.
Mol Genet Metab 2005 Jun
PMID:Biochemical and genetic characterization of four cases of hereditary coproporphyria in Spain. 1589 62


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