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PDBsum entry 3o2g
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Oxidoreductase
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PDB id
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3o2g
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References listed in PDB file
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Key reference
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Title
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Structural and mechanistic studies on γ-Butyrobetaine hydroxylase.
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Authors
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I.K.Leung,
T.J.Krojer,
G.T.Kochan,
L.Henry,
F.Von delft,
T.D.Claridge,
U.Oppermann,
M.A.Mcdonough,
C.J.Schofield.
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Ref.
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Chem Biol, 2010,
17,
1316-1324.
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PubMed id
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Abstract
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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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