First-principles study of non-heme Fe(II) halogenase SyrB2 reactivity
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jacs-hjk-manuscriptfinal.pdf
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Author(s)
Kulik, Heather Janine
Blasiak, Leah C.
Marzari, Nicola
Drennan, Catherine L.
Date Issued
September 2009
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Kulik, Heather J. et al. “First-Principles Study of Non-heme Fe(II) Halogenase SyrB2 Reactivity.” Journal of the American Chemical Society 131 (2009): 14426-14433. Web. 15 Dec. 2011. © 2011 American Chemical Society
Version
Author's final manuscript
Abstract
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.
Description
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/ja905206k
