Genomes and Genes
Gene Symbol: Fech
Alias: AI894116, Fcl, fch, ferrochelatase, mitochondrial, heme synthase, heme synthetase, protoheme ferro-lyase
- Boulechfar S, Lamoril J, Montagutelli X, Guenet J, Deybach J, Nordmann Y, et al. Ferrochelatase structural mutant (Fechm1Pas) in the house mouse. Genomics. 1993;16:645-8 pubmed..This Fechm1Pas/Fechm1Pas mutant mouse represents a useful model for studying the pathophysiological feature of the human disease and the first accessible model for gene therapy in the field of porphyrias. ..
- Sellers V, Johnson M, Dailey H. Function of the [2FE-2S] cluster in mammalian ferrochelatase: a possible role as a nitric oxide sensor. Biochemistry. 1996;35:2699-704 pubmed..The potential physiological relevance of these data to the anemias that are found in individuals with chronic infections is discussed. ..
- Drissen R, von Lindern M, Kolbus A, Driegen S, Steinlein P, Beug H, et al. The erythroid phenotype of EKLF-null mice: defects in hemoglobin metabolism and membrane stability. Mol Cell Biol. 2005;25:5205-14 pubmed..Our data provide an explanation for the hitherto unexplained severity of the EKLF null phenotype in erythropoiesis. ..
- Franco R, Bai G, Prosinecki V, Abrunhosa F, Ferreira G, Bastos M. Porphyrin-substrate binding to murine ferrochelatase: effect on the thermal stability of the enzyme. Biochem J. 2005;386:599-605 pubmed..However, in contrast with the wild-type enzyme, the thermal denaturation of ferrochelatase variants was best described as a non-co-operative denaturation process. ..
- Libbrecht L, Meerman L, Kuipers F, Roskams T, Desmet V, Jansen P. Liver pathology and hepatocarcinogenesis in a long-term mouse model of erythropoietic protoporphyria. J Pathol. 2003;199:191-200 pubmed..present in the livers of 44 mice with a heterozygous or homozygous point mutation in the ferrochelatase gene (fch/+ and fch/fch mice, respectively). Some fch/+ mouse livers showed mixed steatosis and large cell dysplasia...
- Taketani S, Ishigaki M, Mizutani A, Uebayashi M, Numata M, Ohgari Y, et al. Heme synthase (ferrochelatase) catalyzes the removal of iron from heme and demetalation of metalloporphyrins. Biochemistry. 2007;46:15054-61 pubmed..This is the first demonstration of a new enzyme reaction, the reverse reaction of ferrochelatase, which may contribute to a new route of the recycling of protoporphyrin and heme in cells. ..
- Hunter G, Sampson M, Ferreira G. Metal ion substrate inhibition of ferrochelatase. J Biol Chem. 2008;283:23685-91 pubmed publisher..These data indicate the presence of two catalytically significant metal ion binding sites that may coordinately regulate a selective processivity for the various potential metal ion substrates. ..
- Crooks D, Ghosh M, Haller R, Tong W, Rouault T. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood. 2010;115:860-9 pubmed publisher..We propose that decreased heme biosynthesis resulting from impaired Fe-S cluster assembly can contribute to the pathogenesis of diseases caused by defective Fe-S cluster biogenesis...
- Tallack M, Whitington T, Yuen W, Wainwright E, Keys J, Gardiner B, et al. A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells. Genome Res. 2010;20:1052-63 pubmed publisher..Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment...
- Taketani S, Fujita H. The ferrochelatase gene structure and molecular defects associated with erythropoietic protoporphyria. J Bioenerg Biomembr. 1995;27:231-8 pubmedFerrochelatase [heme synthase, protoheme ferrolyase (EC 220.127.116.11)], the terminal enzyme of the heme biosynthetic pathway, catalyzes the incorporation of ferrous ion into protoporphyrin IX to form protoheme IX...
- Fukuda Y, Cheong P, Lynch J, Brighton C, Frase S, Kargas V, et al. The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6. Nat Commun. 2016;7:12353 pubmed publisher..Accordingly, homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes in the Fech(m1Pas) mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury...
- Bannerman R, Edwards J, Pinkerton P. Hereditary disorders of the red cell in animals. Prog Hematol. 1973;8:131-79 pubmed
- Szefczyk B, Cordeiro M, Franco R, Gomes J. Molecular dynamics simulations of mouse ferrochelatase variants: what distorts and orientates the porphyrin?. J Biol Inorg Chem. 2009;14:1119-28 pubmed publisher..The function of residues coordinating propionate groups of the haem molecule is discussed in terms of stability of the substrate and product complexes. ..
- Shi Z, Ferreira G. Modulation of inhibition of ferrochelatase by N-methylprotoporphyrin. Biochem J. 2006;399:21-8 pubmed..Collectively, these results suggest that Pro255 has a crucial role in maintaining an appropriate protein conformation and modulating the selectivity and/or regiospecificity of ferrochelatase. ..
- Brenner D, Frasier F. Cloning of murine ferrochelatase. Proc Natl Acad Sci U S A. 1991;88:849-53 pubmed..The cloning of murine ferrochelatase cDNAs provides the basis for future studies on ferrochelatase gene expression and on the identification of the molecular defect in protoporphyria. ..
- Chernova T, Nicotera P, Smith A. Heme deficiency is associated with senescence and causes suppression of N-methyl-D-aspartate receptor subunits expression in primary cortical neurons. Mol Pharmacol. 2006;69:697-705 pubmed..Culture of cortical neurons from BALB/c Fech(m1Pas) mutant mice demonstrating depressed heme synthesis showed premature senescence and reduced expression of ..
- Han A, Fleming M, Chen J. Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest. 2005;115:1562-70 pubmed..Our findings also demonstrate that translational regulation could play a critical role in the clinical manifestation of rbc diseases. ..
- Dailey H, Sellers V, Dailey T. Mammalian ferrochelatase. Expression and characterization of normal and two human protoporphyric ferrochelatases. J Biol Chem. 1994;269:390-5 pubmed..Elimination of the carboxyl-terminal 30 amino acid residues (which include Phe-417) results in a protein the same length as the bacterial ferrochelatases, but it is an inactive enzyme. ..
- Abitbol M, Bernex F, Puy H, Jouault H, Deybach J, Guenet J, et al. A mouse model provides evidence that genetic background modulates anemia and liver injury in erythropoietic protoporphyria. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1208-16 pubmed..They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences and to identify modifying genes. ..
- Davies R, Schuurman A, Barker C, Clothier B, Chernova T, Higginson F, et al. Hepatic gene expression in protoporphyic Fech mice is associated with cholestatic injury but not a marked depletion of the heme regulatory pool. Am J Pathol. 2005;166:1041-53 pubmedBALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria...
- Crouse B, Sellers V, Finnegan M, Dailey H, Johnson M. Site-directed mutagenesis and spectroscopic characterization of human ferrochelatase: identification of residues coordinating the [2Fe-2S] cluster. Biochemistry. 1996;35:16222-9 pubmed..Such anomalous coordination could account for the cluster lability compared to similar clusters with complete cysteinyl ligation and hence may be intrinsic to the proposed regulatory role for this cluster in mammalian ferrochelatases. ..
- Taketani S, Mohri T, Hioki K, Tokunaga R, Kohno H. Structure and transcriptional regulation of the mouse ferrochelatase gene. Gene. 1999;227:117-24 pubmed..It appears that at least two promoter regions of the mouse ferrochelatase gene function in basic and inducible expression. ..
- Bloks V, Plosch T, van Goor H, Roelofsen H, Baller J, Havinga R, et al. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J Lipid Res. 2001;42:41-50 pubmed..we have analyzed hepatic lipid content and plasma lipoprotein levels in chow-fed BALB/c mice homozygous ( fch/fch) or heterozygous ( fch/1) for a point mutation in the ferrochelatase gene and in wild-type controls (1/1)...
- Sakaino M, Kataoka T, Taketani S. Post-transcriptional regulation of the expression of ferrochelatase by its variant mRNA. J Biochem. 2009;145:733-8 pubmed publisherFerrochelatase (FECH) catalyses the insertion of ferrous ions into protoporphyrin IX to produce haem at the haem-biosynthetic pathway...
- Lu Y, Sousa A, Franco R, Mangravita A, Ferreira G, Moura I, et al. Binding of protoporphyrin IX and metal derivatives to the active site of wild-type mouse ferrochelatase at low porphyrin-to-protein ratios. Biochemistry. 2002;41:8253-62 pubmed..Moreover, RR data reveal the presence of an amino acid residue in the active site of ferrochelatase which is capable of specific axial ligation to metals. ..
- Tian M, Campagna D, Woodward L, Justice M, Fleming M. hem6: an ENU-induced recessive hypochromic microcytic anemia mutation in the mouse. Blood. 2008;112:4308-13 pubmed publisher..Overall, these data lead to the hypothesis that hem6 encodes a protein that directly or indirectly regulates the expression of Alas2. ..
- Magness S, Maeda N, Brenner D. An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria. Blood. 2002;100:1470-7 pubmed..Heterozygous mice exhibited skin photosensitivity but no liver disease. These results lend support for a dominant-negative effect of a mutant allele on ferrochelatase activity in patients with protoporphyria. ..
- Yamamoto M, Arimura H, Fukushige T, Minami K, Nishizawa Y, Tanimoto A, et al. Abcb10 role in heme biosynthesis in vivo: Abcb10 knockout in mice causes anemia with protoporphyrin IX and iron accumulation. Mol Cell Biol. 2014;34:1077-84 pubmed publisher..reportedly a part of a complex in the mitochondrial inner membrane with mitoferrin-1 (Slc25a37) and ferrochelatase (Fech) and is responsible for heme biosynthesis in utero...
- Karlberg T, Hansson M, Yengo R, Johansson R, Thorvaldsen H, Ferreira G, et al. Porphyrin binding and distortion and substrate specificity in the ferrochelatase reaction: the role of active site residues. J Mol Biol. 2008;378:1074-83 pubmed publisher..Collectively, these results provide new insights into the role of the active site residues of ferrochelatase in controlling stereospecificity, distortion and metallation. ..
- Shi Z, Ferreira G. Probing the active site loop motif of murine ferrochelatase by random mutagenesis. J Biol Chem. 2004;279:19977-86 pubmed..However, despite the plasticity of the loop primary structure, the relative spatial positioning of the loop in the active site appeared to be maintained in functional variants, supporting a role for the loop in ferrochelatase function. ..
- Ferreira G. Ferrochelatase binds the iron-responsive element present in the erythroid 5-aminolevulinate synthase mRNA. Biochem Biophys Res Commun. 1995;214:875-8 pubmed..This IRE-binding activity of ferrochelatase may play a critical role in the regulation of heme biosynthesis in differentiating erythrocytes. ..
- Tutois S, Montagutelli X, Da Silva V, Jouault H, Rouyer Fessard P, Leroy Viard K, et al. Erythropoietic protoporphyria in the house mouse. A recessive inherited ferrochelatase deficiency with anemia, photosensitivity, and liver disease. J Clin Invest. 1991;88:1730-6 pubmedA viable autosomal recessive mutation (named fch, or ferrochelatase deficiency) causing jaundice and anemia in mice arose in a mutagenesis experiment using ethylnitrosourea...
- Taketani S, Nakahashi Y, Osumi T, Tokunaga R. Molecular cloning, sequencing, and expression of mouse ferrochelatase. J Biol Chem. 1990;265:19377-80 pubmed..The band pattern of the RNA of the mouse liver was the same as that of the MEL cells. Based on these results, we deduce that ferrochelatase in erythroid and hepatic cells can be only of one type. ..
- Ning B, Liu G, Liu Y, Su X, Anderson G, Zheng X, et al. 5-aza-2'-deoxycytidine activates iron uptake and heme biosynthesis by increasing c-Myc nuclear localization and binding to the E-boxes of transferrin receptor 1 (TfR1) and ferrochelatase (Fech) genes. J Biol Chem. 2011;286:37196-206 pubmed publisher..induced erythroid differentiation and increased the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech), thereby increasing iron uptake and heme biosynthesis...
- Navarro S, Meza N, Quintana Bustamante O, Casado J, Jacome A, McAllister K, et al. Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Mol Ther. 2006;14:525-35 pubmed..The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy. ..
- Lyoumi S, Abitbol M, Andrieu V, Henin D, Robert E, Schmitt C, et al. Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice. Blood. 2007;109:811-8 pubmedPatients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive ..
- Chen W, Dailey H, Paw B. Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood. 2010;116:628-30 pubmed publisher..either Mfrn1-FLAG or Abcb10-FLAG and by affinity purification and mass spectrometry have identified ferrochelatase (Fech) as an interacting protein for both Mfrn1 and Abcb10...
- Ferreira G. Ferrochelatase. Int J Biochem Cell Biol. 1999;31:995-1000 pubmed..The definition of the structure and catalytic mechanism of ferrochelatase should help in the interpretation of the impact caused by erythropoietic porphyria mutations. ..
- Shi Z, Franco R, Haddad R, Shelnutt J, Ferreira G. The conserved active-site loop residues of ferrochelatase induce porphyrin conformational changes necessary for catalysis. Biochemistry. 2006;45:2904-12 pubmed..These results suggest that specific conserved loop residues (especially Trp256) are directly involved in the saddling of the porphyrin substrate. ..
- Magness S, Brenner D. Targeted disruption of the mouse ferrochelatase gene producing an exon 10 deletion. Biochim Biophys Acta. 1999;1453:161-74 pubmed..This suggests that requirement of an additional mutation to decrease the expression of the wild-type allele. ..