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Structural and Mechanistic Studies on γ-Butyrobetaine Hydroxylase
DOI:
10.1016/j.chembiol.2010.09.016
PMID:
21168767
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
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