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...

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Main Authors: Leung, I, Krojer, T, Kochan, G, Henry, L, von Delft, F, Claridge, T, Oppermann, U, McDonough, M, Schofield, C
Formato: Journal article
Idioma:English
Publicado: 2010
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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.
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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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AT krojert structuralandmechanisticstudiesongbutyrobetainehydroxylase
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AT henryl structuralandmechanisticstudiesongbutyrobetainehydroxylase
AT vondelftf structuralandmechanisticstudiesongbutyrobetainehydroxylase
AT claridget structuralandmechanisticstudiesongbutyrobetainehydroxylase
AT oppermannu structuralandmechanisticstudiesongbutyrobetainehydroxylase
AT mcdonoughm structuralandmechanisticstudiesongbutyrobetainehydroxylase
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