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Structural and Mechanistic Studies on γ-Butyrobetaine Hydroxylase

DOI: 10.1016/j.chembiol.2010.09.016 DOI Help
PMID: 21168767 PMID Help

Authors: Ivanhoe K.h. Leung (University of Oxford) , Tobias Krojer (Oxford University SGC) , Grazyna Kochan (University of Oxford) , Luc Henry (University of Oxford) , Frank Von Delft (University of Oxford) , Timothy D.w. Claridge (University of Oxford) , Udo Oppermann (University of Oxford) , Michael Mcdonough (Department of Chemistry, University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 17 (12) , PAGES 1316 - 1324

State: Published (Approved)
Published: December 2010
Diamond Proposal Number(s): 442

Abstract: The final step in carnitine biosynthesis is catalyzed by gamma-butyrobetaine (gamma BB) hydroxylase (BBOX), an iron/2-oxoglutarate (2OG) dependent oxygenase. BBOX is inhibited by trimethylhydrazine-propionate (THP), a clinically used compound. We report structural and mechanistic studies on BBOX and its reaction with THP. Crystallographic and sequence analyses reveal that BBOX and trimethyllysine hydroxylase form a subfamily of 2OG oxygenases that dimerize using an N-terminal domain. The crystal structure reveals the active site is enclosed and how THP competes with gamma BB. THP is a substrate giving formaldehyde (supporting structural links with histone demethylases), dimethylamine, malonic acid semi-aldehyde, and an unexpected product with an additional carbon-carbon bond resulting from N-demethylation coupled to oxidative rearrangement, likely via an unusual radical mechanism. The results provide a basis for development of improved BBOX inhibitors and may inspire the discovery of additional rearrangement reactions.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 01/10/2011 17:46

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