期刊
CHEMISTRY & BIOLOGY
卷 17, 期 12, 页码 1316-1324出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2010.09.016
关键词
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资金
- Engineering and Physical Sciences Research Council
- Berrow Foundation
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust [1097737]
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation [1097737]
- Genome Canada through the Ontario Genomics Institute [1097737]
- GlaxoSmithKline [1097737]
- Karolinska Institutet [1097737]
- Knut and Alice Wallenberg Foundation [1097737]
- Ontario Innovation Trust [1097737]
- Ontario Ministry for Research and Innovation [1097737]
- Merck Co., Inc. [1097737]
- Novartis Research Foundation [1097737]
- Swedish Foundation for Strategic Research [1097737]
- NIHR Biomedical Research Unit
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.
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