Structural and mechanistic studies on γ-butyrobetaine hydroxylase.
The final step in carnitine biosynthesis is catalyzed by γ-butyrobetaine (γBB) 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 reac...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2010
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| _version_ | 1797068077212368896 |
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| author | Leung, I Krojer, T Kochan, G Henry, L von Delft, F Claridge, T Oppermann, U McDonough, M Schofield, C |
| author_facet | Leung, I Krojer, T Kochan, G Henry, L von Delft, F Claridge, T Oppermann, U McDonough, M Schofield, C |
| author_sort | Leung, I |
| collection | OXFORD |
| description | The final step in carnitine biosynthesis is catalyzed by γ-butyrobetaine (γBB) 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 γBB. 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. |
| first_indexed | 2024-03-06T22:05:33Z |
| format | Journal article |
| id | oxford-uuid:500510e6-5eaf-484a-abeb-86fc8176b291 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:05:33Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:500510e6-5eaf-484a-abeb-86fc8176b2912022-03-26T16:11:08ZStructural and mechanistic studies on γ-butyrobetaine hydroxylase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:500510e6-5eaf-484a-abeb-86fc8176b291CarnitinechemistryCrystallography, X-Raygamma-Butyrobetaine DioxygenaseSubstrate SpecificitybiosynthesisCatalytic DomainmetabolismProtein Structure, QuaternaryDimerizationProtein Structure, TertiaryEnglishStructural Genomics Consortium2010Leung, IKrojer, TKochan, GHenry, Lvon Delft, FClaridge, TOppermann, UMcDonough, MSchofield, CThe final step in carnitine biosynthesis is catalyzed by γ-butyrobetaine (γBB) 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 γBB. 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. |
| spellingShingle | Carnitine chemistry Crystallography, X-Ray gamma-Butyrobetaine Dioxygenase Substrate Specificity biosynthesis Catalytic Domain metabolism Protein Structure, Quaternary Dimerization Protein Structure, Tertiary Leung, I Krojer, T Kochan, G Henry, L von Delft, F Claridge, T Oppermann, U McDonough, M Schofield, C Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title | Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title_full | Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title_fullStr | Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title_full_unstemmed | Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title_short | Structural and mechanistic studies on γ-butyrobetaine hydroxylase. |
| title_sort | structural and mechanistic studies on γ butyrobetaine hydroxylase |
| topic | Carnitine chemistry Crystallography, X-Ray gamma-Butyrobetaine Dioxygenase Substrate Specificity biosynthesis Catalytic Domain metabolism Protein Structure, Quaternary Dimerization Protein Structure, Tertiary |
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