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dc.contributor.authorSakipov, Serzhan
dc.contributor.authorRafikova, Olga
dc.contributor.authorKurnikova, Maria G.
dc.contributor.authorRafikov, Ruslan
dc.date.accessioned2017-06-23T21:38:34Z
dc.date.available2017-06-23T21:38:34Z
dc.date.issued2017-04
dc.identifier.citationMolecular mechanisms of bio-catalysis of heme extraction from hemoglobin 2017, 11:516 Redox Biologyen
dc.identifier.issn22132317
dc.identifier.pmid28088643
dc.identifier.doi10.1016/j.redox.2017.01.004
dc.identifier.urihttp://hdl.handle.net/10150/624355
dc.description.abstractRed 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.
dc.description.sponsorshipAmerican Heart Association National Office [14SDG20480354]; NIH [R01HL132918]en
dc.language.isoenen
dc.publisherELSEVIER SCIENCE BVen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S2213231717300095en
dc.rights© 2017 The Authors. Published by Elsevier B.V.en
dc.subjectSickle cell diseaseen
dc.subjectHeme scavengeren
dc.subjectMolecular dynamics simulationsen
dc.subjectHeme-protein binding modelingen
dc.titleMolecular mechanisms of bio-catalysis of heme extraction from hemoglobinen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Meden
dc.identifier.journalRedox Biologyen
dc.description.noteOpen access journalen
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-09-11T20:24:11Z
html.description.abstractRed 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.


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