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| FECH | |
|---|---|
| Name | Ferrochelatase |
| Uniprot | P21549 |
| Ec | 4.99.1.1 |
| Location | Mitochondrion |
FECH
FECH is a mitochondrial enzyme responsible for inserting ferrous iron into protoporphyrin IX to form heme, a process essential for hemoprotein biogenesis. Discovered through biochemical and genetic studies that involved researchers at institutions such as Max Planck Society, Harvard University, and University of Oxford, the enzyme has been characterized structurally and functionally by X-ray crystallography groups at European Molecular Biology Laboratory and Riken. FECH connects to pathways studied by investigators affiliated with National Institutes of Health, Massachusetts Institute of Technology, and Karolinska Institutet.
FECH is a homodimeric enzyme localized to the inner membrane of mitochondria and anchored via an N-terminal targeting sequence first analyzed by teams at Johns Hopkins University and Stanford University. Crystallographic models solved by groups at European Synchrotron Radiation Facility and Stanford Synchrotron Radiation Lightsource reveal a conserved alpha/beta fold and a [2Fe-2S] cluster binding motif characterized by studies from Max Planck Institute for Biochemistry and University of Cambridge. Structural comparisons with ferrochelatases from Escherichia coli, Saccharomyces cerevisiae, and Arabidopsis thaliana show conserved active-site residues and a substrate-binding pocket identified in work at University of California, Berkeley and University of Tokyo. Functional assays performed in laboratories at University of Pennsylvania and Yale University established that the enzyme catalyzes metal insertion with stereospecificity and metal selectivity, as probed by investigators at University of Chicago and Columbia University.
The FECH gene was mapped and cloned in studies involving geneticists at National Human Genome Research Institute and Wellcome Trust Sanger Institute. Genetic variants identified by consortia such as 1000 Genomes Project and Exome Aggregation Consortium include loss-of-function alleles and promoter polymorphisms reported by teams at University College London and University of Edinburgh. Expression profiling across tissues by the Genotype-Tissue Expression Project and microarray studies from Fred Hutchinson Cancer Research Center indicate high transcript levels in hematopoietic tissues and liver, with regulation during erythropoiesis documented by researchers at University of Barcelona and McGill University. Transcriptional control elements were characterized in studies at Cold Spring Harbor Laboratory and Institute of Molecular Biology (Austria), while splice variant analyses were reported by groups at University of Toronto and University of Milan.
FECH catalyzes the terminal step in the heme biosynthetic pathway, interfacing with enzymes such as those encoded by ALAS1, PPOX, and UROD as revealed in pathway reconstructions from KEGG and modeling studies at European Bioinformatics Institute. Heme produced by FECH is critical for hemoglobin assembly in erythrocytes, a process explored by investigators at University of Oxford and University of Cambridge in studies of red cell development. Mitochondrial heme export and incorporation into cytochromes were subjects of work at Max Planck Institute for Heart and Lung Research and Johns Hopkins University School of Medicine, linking FECH activity to respiratory chain components analyzed by teams at Salk Institute and Imperial College London. Evolutionary analyses comparing metazoan, bacterial, and plant ferrochelatases were reported by researchers at University of California, San Diego and University of Göttingen.
Mutations in FECH are associated with erythropoietic protoporphyria and related porphyrias, clinical correlations established by cohorts studied at Mayo Clinic, Cleveland Clinic, and Johns Hopkins Hospital. Diagnostic and therapeutic approaches, including genetic screening programs at National Health Service centers and biochemical assays developed at Molecular Diagnostics Laboratory, University of Washington, are informed by genotype-phenotype studies from Stanford Medical Center and Mount Sinai Hospital. Pharmacologic interactions involving drugs metabolized by hemoproteins have been assessed by groups at Food and Drug Administration and European Medicines Agency, highlighting the enzyme's relevance in adverse drug reactions reported by clinicians at Karolinska University Hospital. Bone marrow transplantation outcomes and gene therapy prospects were investigated in preclinical studies at St. Jude Children's Research Hospital and clinical trials coordinated by European Hematology Association investigators.
FECH interacts with mitochondrial transporters, chaperones, and partners such as ABCB10, identified in proteomics screens by laboratories at Max Planck Institute of Molecular Cell Biology and Genetics and Broad Institute. Post-translational modifications, including phosphorylation and proteolytic processing, were characterized in phosphoproteomic studies conducted by teams at Proteome Sciences and EMBL-EBI. The [2Fe-2S] cluster assembly pathway components, such as ISCU and frataxin, were shown to modulate FECH activity in mechanistic studies at University of California, San Francisco and ETH Zurich. Regulation by iron-responsive signaling and erythropoietic factors was described in papers from University of Copenhagen and Monash University.
FECH ortholog function has been probed in model organisms including Saccharomyces cerevisiae, Drosophila melanogaster, Mus musculus, and Danio rerio, with phenotypes analyzed by groups at European Molecular Biology Laboratory, Howard Hughes Medical Institute, and University of Basel. Knockout and knockdown studies in mice and zebrafish, carried out at The Jackson Laboratory and Max Planck Institute for Biology of Ageing, revealed defects in erythropoiesis and mitochondrial function. Chemical biology approaches using inhibitors and substrate analogs were developed in collaborations between researchers at Pfizer and academic laboratories at University of Freiburg. High-resolution structural studies combined with mutagenesis experiments were reported by consortia including Structural Genomics Consortium and teams at RCSB Protein Data Bank contributors.
Category:Enzymes