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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Formato: | Journal article |
Idioma: | English |
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2010
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_version_ | 1826279790100873216 |
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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 | 2024-03-07T00:04:02Z |
format | Journal article |
id | oxford-uuid:76f0eda3-b702-405f-9a40-e2ee0a50a6e6 |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-07T00:04:02Z |
publishDate | 2010 |
record_format | dspace |
spelling | oxford-uuid:76f0eda3-b702-405f-9a40-e2ee0a50a6e62022-03-26T20:19:46ZStructural and mechanistic studies on γ-butyrobetaine hydroxylase.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:76f0eda3-b702-405f-9a40-e2ee0a50a6e6EnglishSymplectic Elements at Oxford2010Leung, 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 | 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 |
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