Molecular mechanisms of bio-catalysis of heme extraction from hemoglobin
AffiliationUniv Arizona, Dept Med
KeywordsSickle cell disease
Molecular dynamics simulations
Heme-protein binding modeling
MetadataShow full item record
PublisherELSEVIER SCIENCE BV
CitationMolecular mechanisms of bio-catalysis of heme extraction from hemoglobin 2017, 11:516 Redox Biology
Rights© 2017 The Authors. Published by Elsevier B.V.
Collection InformationThis 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 firstname.lastname@example.org.
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.
NoteOpen access journal
VersionFinal published version
SponsorsAmerican Heart Association National Office [14SDG20480354]; NIH [R01HL132918]
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