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    Molecular mechanisms of bio-catalysis of heme extraction from hemoglobin

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    Author
    Sakipov, Serzhan
    Rafikova, Olga
    Kurnikova, Maria G.
    Rafikov, Ruslan
    Affiliation
    Univ Arizona, Dept Med
    Issue Date
    2017-04
    Keywords
    Sickle cell disease
    Heme scavenger
    Molecular dynamics simulations
    Heme-protein binding modeling
    
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    Show full item record
    Publisher
    ELSEVIER SCIENCE BV
    Citation
    Molecular mechanisms of bio-catalysis of heme extraction from hemoglobin 2017, 11:516 Redox Biology
    Journal
    Redox Biology
    Rights
    © 2017 The Authors. Published by Elsevier B.V.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. We propose an approach that helps to eliminate extracellular hemoglobin toxicity in SCD by employing a bacterial protein system that evolved to extract heme from extracellular hemoglobin. NEAr heme Transporter (NEAT) domains from iron-regulated surface determinant proteins from Staphylococcus aureus specifically bind free heme as well as facilitate its extraction from hemoglobin. We demonstrate that a purified NEAT domain fused with human haptoglobin beta-chain is able to remove heme from hemoglobin and reduce heme content and peroxidase activity of hemoglobin. We further use molecular dynamics (MD) simulations to resolve molecular pathway of heme transfer from hemoglobin to NEAT, and to elucidate molecular mechanism of such heme transferring process. Our study is the first of its kind, in which simulations are employed to characterize the process of heme leaving hemoglobin and subsequent rebinding with a NEAT domain. Our MD results highlight important amino acid residues that facilitate heme transfer and will guide further studies for the selection of best NEAT candidate to attenuate free hemoglobin toxicity.
    Note
    Open access journal
    ISSN
    22132317
    PubMed ID
    28088643
    DOI
    10.1016/j.redox.2017.01.004
    Version
    Final published version
    Sponsors
    American Heart Association National Office [14SDG20480354]; NIH [R01HL132918]
    Additional Links
    http://linkinghub.elsevier.com/retrieve/pii/S2213231717300095
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.redox.2017.01.004
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