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03798 am a22003253u 4500 |
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|a Kulik, Heather Janine
|e author
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|a Massachusetts Institute of Technology. Department of Biology
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|a Massachusetts Institute of Technology. Department of Chemistry
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|a Massachusetts Institute of Technology. Department of Materials Science and Engineering
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|a Drennan, Catherine L
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|a Kulik, Heather Janine
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|a Blasiak, Leah C.
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|a Marzari, Nicola
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|a Drennan, Catherine L.
|e contributor
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|a Blasiak, Leah C.
|e author
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|a Marzari, Nicola
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|a Drennan, Catherine L.
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|a First-principles study of non-heme Fe(II) halogenase SyrB2 reactivity
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|b American Chemical Society,
|c 2011-12-15T19:09:46Z.
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| 856 |
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|z Get fulltext
|u http://hdl.handle.net/1721.1/67699
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|a GGA+U methodology details and explanation, linear-response U values, U dependent splittings, bond lengths, reaction steps, dissociation energies, occupation matrices and oxidation states, and additional structural parameters. This material is available free of charge via the Internet at http://pubs.acs.org.
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|a We present here a computational study of reactions at a model complex of the SyrB2 enzyme active site. SyrB2, which chlorinates l-threonine in the syringomycin biosynthetic pathway, belongs to a recently discovered class of α-ketoglutarate (αKG), non-heme Fe(II)-dependent halogenases that share many structural and chemical similarities with hydroxylases. Namely, halogenases and hydroxylases alike decarboxylate the αKG co-substrate, facilitating formation of a high-energy ferryl-oxo intermediate that abstracts a hydrogen from the reactant complex. The reaction mechanisms differ at this point, and mutation of active site residues (Asp for the hydroxylase to Ala or Ala to Asp/Glu for halogenase) fails to reproduce hydroxylating activity in SyrB2 or halogenating activity in similar hydroxylases. Using a density functional theory approach with a recently implemented Hubbard U correction for accurate treatment of transition-metal chemistry, we explore probable reaction pathways and mechanisms via a model complex consisting of only the iron center and its direct ligands. We show that the first step, αKG decarboxylation, is barrierless and exothermic, but the subsequent hydrogen abstraction step has an energetic barrier consistent with that accessible under biological conditions. In the model complex we use, radical chlorination is barrierless and exothermic, whereas the analogous hydroxylation is found to have a small energetic barrier. The hydrogen abstraction and radical chlorination steps are strongly coupled: the barrier for the hydrogen abstraction step is reduced when carried out concomitantly with the exothermic chlorination step. Our work suggests that the lack of chlorination in mutant hydroxylases is most likely due to poor binding of chlorine in the active site, whereas mutant halogenases do not hydroxylate for energetic reasons. Although secondary shell residues undoubtedly modulate the overall reactivity and binding of relevant substrates, we show that a small model compound consisting exclusively of the direct ligands to the metal can help explain reactivity heretofore not yet understood in the halogenase SyrB2.
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|a National Institutes of Health (U.S.) (GM65337)
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|a National Institutes of Health (U.S.) (T32-GM08334)
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|a United States. Dept. of Energy (DE-AC04-94AL850000)
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|a en_US
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|a Article
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|t Journal of the American Chemical Society
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