Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Mutations and a low-expressed allele IVS3-48c (in trans to the mutation) of the ferrochelatase (FECH) gene are responsible for erythropoietic protoporphyria (EPP) which is characterized clinically by cutaneous photosensitivity. In this study of 15 Italian EPP families, we identified 10 different FECH gene mutations, six of them were novel mutations (Q32X; IVS2-2, a-->g; IVS3-67, g-->a; 488-501del 14bp; IVS5-3, c-->t and 757-761delAGAAG). Four were known mutations (213insT; R115X; S264L and 899-900delTG). Real-time PCR quantification of FECH mRNA from a patient carrying mutation IVS-67, g-->a revealed a 51% reduction in the normal FECH transcript. This mutation generated an abnormal mRNA species with a 63-bp intron 3 retention--the same mRNA species which the low-expressed FECH allele IVS3-48c also produces. In addition, a double intronic deletion (IVS8-61 del ag /IVS9-58 del a) was found in some patients as well as their healthy relatives of this cohort. Sequencing of 50 Italian control subjects revealed an 11% prevalence of the double deletion. However, the double intronic deletion is not a disease-causing mutation as evidenced by a normal amount of FECH mRNA measured from a non-porphyric individual who carried the double deletion. Another interesting finding of this study was a 1% prevalence of IVS3-48c allele in the white Italian population, comparing to 11% in the French population. Further epidemiological studies are needed to test whether the 1% frequency of the low-expressed IVS3-48c allele is associated with a low prevalence of EPP in the white Italian population.
Mol Genet Metab 2007 Apr
PMID:Heterogeneity of mutations in the ferrochelatase gene in Italian patients with erythropoietic protoporphyria. 1719 62

Ferrochelatase (protoheme ferrolyase, EC 4.99.1.1) is the terminal enzyme in heme biosynthesis and catalyzes the insertion of ferrous iron into protoporphyrin IX to form protoheme IX (heme). Due to the many critical roles of heme, synthesis of heme is required by the vast majority of organisms. Despite significant investigation of both the microbial and eukaryotic enzyme, details of metal chelation remain unidentified. Here we present the first structure of the wild-type human enzyme, a lead-inhibited intermediate of the wild-type enzyme with bound metallated porphyrin macrocycle, the product bound form of the enzyme, and a higher resolution model for the substrate-bound form of the E343K variant. These data paint a picture of an enzyme that undergoes significant changes in secondary structure during the catalytic cycle. The role that these structural alterations play in overall catalysis and potential protein-protein interactions with other proteins, as well as the possible molecular basis for these changes, is discussed. The atomic details and structural rearrangements presented herein significantly advance our understanding of the substrate binding mode of ferrochelatase and reveal new conformational changes in a structurally conserved pi-helix that is predicted to have a central role in product release.
J Mol Biol 2007 Nov 02
PMID:A pi-helix switch selective for porphyrin deprotonation and product release in human ferrochelatase. 1788 90

The specific insertion of a divalent metal ion into tetrapyrrole macrocycles is catalyzed by a group of enzymes called chelatases. Distortion of the tetrapyrrole has been proposed to be an important component of the mechanism of metallation. We present the structures of two different inhibitor complexes: (1) N-methylmesoporphyrin (N-MeMP) with the His183Ala variant of Bacillus subtilis ferrochelatase; (2) the wild-type form of the same enzyme with deuteroporphyrin IX 2,4-disulfonic acid dihydrochloride (dSDP). Analysis of the structures showed that only one N-MeMP isomer out of the eight possible was bound to the protein and it was different from the isomer that was earlier found to bind to the wild-type enzyme. A comparison of the distortion of this porphyrin with other porphyrin complexes of ferrochelatase and a catalytic antibody with ferrochelatase activity using normal-coordinate structural decomposition reveals that certain types of distortion are predominant in all these complexes. On the other hand, dSDP, which binds closer to the protein surface compared to N-MeMP, does not undergo any distortion upon binding to the protein, underscoring that the position of the porphyrin within the active site pocket is crucial for generating the distortion required for metal insertion. In addition, in contrast to the wild-type enzyme, Cu(2+)-soaking of the His183Ala variant complex did not show any traces of porphyrin metallation. Collectively, these results provide new insights into the role of the active site residues of ferrochelatase in controlling stereospecificity, distortion and metallation.
J Mol Biol 2008 May 16
PMID:Porphyrin binding and distortion and substrate specificity in the ferrochelatase reaction: the role of active site residues. 1842 89

Erythropoietic Protoporphyria (EPP) is an inherited deficiency of ferrochelatase, the last enzyme of the heme pathway. Under general anaesthesia, some patients develop neurological dysfunction suggesting upregulation in heme biosynthesis similar to that described for acute porphyrias after xenobiotic administration. Our aim has been to evaluate whether Isoflurane induces alterations in the heme pathway in a mouse model for EPP. Administration of Isoflurane (a single dose of 2 ml/kg, i.p) to wild-type (+/+), heterozygous (+/Fechm1Pas) and homozygous (Fechm1Pas/Fechm1Pas) mice, was evaluated by measuring the activity of delta-aminolevulinic acid synthetase (ALA-S) and Porphobilinogen-deaminase (PBG-D) in different tissues, as well as Heme oxygenase (HO), cytochrome P-450, CYP2E1 and glutathione levels in liver. Porphyrin precursors were measured in 24 h-urine samples. Fechm1Pas/Fechm1Pas mice receiving anaesthesia show enhanced ALA-S and CYP2E1 activities in the liver and increased urinary excretion of porphyrin precursors. No alterations were found in either PBG-D or HO activities. Diminished glutathione levels suggest that anaesthesia may produce oxidative stress in these animals. In conclusion, Isoflurane induces ALA-S activity and increased excretion of porphyrin precursors in EPP mice. These findings appear to confirm our previous hypothesis and indicate that Isoflurane may be an unsafe anaesthetic not only for patients with acute porphyrias but also for individuals with non acute porphyrias.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Induction of hepatic aminolevulinate acid synthetase activity by isoflurane in a genetic model for erythropoietic protoporphyria. 1926

Partial deficiency of the last enzyme of the heme biosynthetic pathway (namely ferrochelatase, FECH) in humans is responsible for erythropoietic protoporphyria (EPP). This disorder is characterised by painful photosensitivity, due to excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial hypotheses have been proposed to explain the hematologic and iron status of EPP patients. In the present work, we explored these parameters in 55 patients with dominant EPP recruited at the French Center of Porphyrias (Colombes, France) and confirmed by molecular analysis. Our data show that erythrocyte accumulation of PPIX in EPP patients influences hematologic and iron status. Patients studied had a mild anemia and thrombocytopenia, as shown by the downward shift of hematologic parameters, which positively correlated with the amount of erythrocyte PPIX. Interestingly, erythropoiesis did not seem to be limited by iron supply in patients, since serum iron and soluble transferring (Tf) receptor (sTfR) were normal. However, iron and Tf saturation negatively correlated with erythrocyte PPIX. Moreover, and as previously described in a mouse model of EPP, we noted a positive correlation between erythrocyte PPIX and Tf levels. Altogether, these results suggest a positive effect of PPIX on the synthesis on Tf, which could facilitate the mobilization of tissue iron stores to meet erythropoiesis requirement. Based on these observations and previous results in EPP mouse model, we propose that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen and the bone marrow.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Excessive erythrocyte PPIX influences the hematologic status and iron metabolism in patients with dominant erythropoietic protoporphyria. 1926 1

In the malarial parasite, enzymes of heme-biosynthetic pathway are distributed in different cellular compartments. The site of localization of ferrochelatase in the malarial parasite is crucial, since it will decide the ultimate site of heme synthesis. Earlier results have differed in terms of localization, being the mitochondrion or apicoplast and the functional enzyme has not been cloned, expressed and characterized. The present study reveals that Plasmodium falciparum ferrochelatase (PfFC) gene encodes multiple transcripts of which the one encoding the full length functional protein (PfFC) has been cloned and the recombinant protein over-expressed and purified from E. coli cells. The enzyme shows maximum activity with iron, while zinc is a poor substrate. Immunofluorescence studies with antibodies to functional ferrochelatase reveal that the native enzyme is localized to the mitochondrion of the parasite indicating that this organelle is the ultimate site of heme synthesis.
Mol Biochem Parasitol 2009 Nov
PMID:Mitochondrial localization of functional ferrochelatase from Plasmodium falciparum. 1952 97

The third intron of human ferrochelatase (FECH) gene contains according to NCBI, a poly-C (11) and a poly-T (24) tracts which are located approximately 900 bp upstream from the known splice modulating SNP IVS3-48 c/t. Ferrochelatase catalyses the last step in heme biosynthesis and a deficiency of this enzyme results in the hereditary disorder of erythropoietic protopoprhyria (EPP). During the course of mutation analysis in the FECH gene among EPP patients, we observed variations in the length of the poly-C and poly-T tracts. To study these variations, we analyzed a total of 54 individuals of Swiss and Israeli origins. Among them, 37 were control subjects (23 individuals with the genotype t/t and 14 with the genotype c/t), 10 were unrelated EPP patients (genotype c/M) and 7 were unrelated asymptomatic mutation carriers (genotype t/M). The length of poly-C tract varied from 10 to 16, that of poly-T tract from 22 to 24 in the study cohort. Statistic analysis showed that the low-expressed FECH allele (IVS3-48c) is associated with poly-C12, C13 and C15 and poly-T22. In addition, the segregation of poly-C and poly-T tracts was studied in two Israeli EPP families. Instabilities, as seen by both insertion and deletion of one nucleotide between two generations, were observed only in the poly-T tract. The function of the poly-C and poly-T tracts are yet to be explored.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Variations in the length of poly-C and poly-T tracts in intron 3 of the human ferrochelatase gene. 1965 58

Erythropoietic protoporphyria (EPP) is an autosomal dominant disorder that results from a deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway. The characteristic clinical symptoms usually manifest in early childhood on the sun-exposed areas of the body. They are due to protoporphyrin-induced photosensitivity and include pain, burning and stinging of the skin, followed by erythema and edema. Recently, the occurrence of predominantly seasonal palmar and palmoplantar keratoderma in patients with homozygous mutations in the FECH gene has been reported. These data suggested that palmoplantar keratoderma might be a clinical sign of EPP. Palmoplantar keratodermas (PPKs) are a heterogeneous group of genetic skin diseases and include a seasonal variant, erythrokeratolysis hiemalis et estivalis (EH), also known as keratolytic winter erythema. Because the skin symptoms in the latter disorder are similar to those reported for recessive EPP we examined the FECH gene in three unrelated Dutch Caucasian patients with a previous diagnosis of EH in whom mutations in several other genes had been excluded. However, sequencing analysis of the entire coding regions and the adjacent splice sites of the FECH gene in these individuals revealed absence of mutations. Hence, our data largely exclude the possibility that FECH mutations might be responsible for the palmoplantar skin phenotype observed in EH.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Exclusion of ferrochelatase gene mutations in patients with seasonal palmoplantar keratoderma. 1965 59

Erythropoietic protoporphyria (EPP) is a syndrome in which accumulation of protoporphyrin IX in erythroid cells, plasma, skin and liver leads to acute photosensitivity and, in about 2% of patients, liver disease. More than 95% of unrelated patients have ferrochelatase (FECH) deficiency (MIM 177000) while about 2% have X-linked dominant protoporphyria (XLDPP) (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene. Most FECH-deficient patients are compound heterozygotes for a hypomorphic allele (FECH IVS3-48C) and a deleterious FECH mutation that together lower FECH activity to around 30% of normal. The frequency of the IVS3-48C allele varies between populations, ranging from less than 1% to 45%. About 4% of unrelated FECH-deficient patients are compound heterozygotes or homozygotes for rare FECH mutations and have lower enzyme activities. Acquired somatic mutation of FECH secondary to myeloid disease may rarely cause EPP. The risk of liver disease is increased in XLDPP and in FECH-deficient patients who are hetero- or homoallelic for rare FECH mutations. Inherited FECH-deficient EPP is an autosomal recessive disorder with some families showing pseudodominant inheritance; the proportion of such families being determined by the population frequency of the IVS3-48C allele.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:The molecular genetics of erythropoietic protoporphyria. 1965 60

Erythropoietic Protoporphyria (EPP) is a disease associated with ferrochelatase deficiency, which produces accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver and skin. In some cases, a severe hepatic failure and cholestasis was observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in animals. The aim of this work was to further characterize this model studying its effect on different metabolisms in mice Gris feeding (0-2.5%, 7 and 14 days). PROTO IX accumulation in liver, blood and feces, induction of ALA-S activity, and a low rate of Holo/Apo tryptophan pyrrolase activity was produced, indicating a reduction of free heme pool. The progressive liver injury was reflected by the aspect and the enlargement of liver and the induction of hepatic damage. Liver redox balance was altered due to porphyrin high concentrations; as a consequence, the antioxidant defense system was disrupted. Heme oxygenase was also induced, however, at higher concentrations of antifungal, the free heme pool would be so depleted that this enzyme would not be necessary. In conclusion, our model of Protoporphyria produced liver alterations similar to those found in EPP patients.
Cell Mol Biol (Noisy-le-grand) 2009 Jul 01
PMID:Hepatic damage and oxidative stress induced by Griseofulvin in mice. 1965 61


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