3hcp
From Proteopedia
Human ferrochelatase with Mn and deuteroporphyrin bound
Structural highlights
Disease[HEMH_HUMAN] Defects in FECH are the cause of erythropoietic protoporphyria (EPP) [MIM:177000]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. EPP is a form of porphyria marked by excessive protoporphyrin in erythrocytes, plasma, liver and feces, and by widely varying photosensitive skin changes ranging from a burning or pruritic sensation to erythema, edema and wheals.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Function[HEMH_HUMAN] Catalyzes the ferrous insertion into protoporphyrin IX. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFerrochelatase (protoheme ferrolyase, E.C. 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). Within the past two years, X-ray crystallographic data obtained with human ferrochelatase have clearly shown that significant structural changes occur during catalysis that are predicted to facilitate metal insertion and product release. One unanswered question about ferrochelatase involves defining the mechanism whereby some metals, such as divalent Fe, Co, Ni, and Zn, can be used by the enzyme in vitro to produce the corresponding metalloporphyrins, while other metals, such as divalent Mn, Hg, Cd, or Pb, are inhibitors of the enzyme. Through the use of high-resolution X-ray crystallography along with characterization of metal species via their anomalous diffraction, the identity and position of Hg, Cd, Ni, or Mn in the center of enzyme-bound porphyrin macrocycle were determined. When Pb, Hg, Cd, or Ni was present in the macrocycle, the conserved pi helix was in the extended, partially unwound "product release" state. Interestingly, in the structure of ferrochelatase with Mn-porphyrin bound, the pi helix is not extended or unwound and is in the "substrate-bound" conformation. These findings show that at least in the cases of Mn, Pb, Cd, and Hg, metal "inhibition" of ferrochelatase is not due to the inability of the enzyme to insert the metal into the macrocycle or by binding to a second metal binding site as has been previously proposed. Rather, inhibition occurs after metal insertion and results from poor or diminished product release. Possible explanations for the lack of product release are proposed herein. Product release rather than chelation determines metal specificity for ferrochelatase.,Medlock AE, Carter M, Dailey TA, Dailey HA, Lanzilotta WN J Mol Biol. 2009 Oct 23;393(2):308-19. Epub 2009 Aug 22. PMID:19703464[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Ferrochelatase | Human | Large Structures | Dailey, H A | Lanzilotta, W N | Medlock, A E | Disease mutation | Heme biosynthesis | Iron | Iron-sulfur | Lyase | Membrane | Metal selectivity | Metal-binding | Mitochondrion | Mitochondrion inner membrane | Porphyrin biosynthesis | Transit peptide
