19 F NMR studies on γ-butyrobetaine hydroxylase provide mechanistic insights and suggest a dual inhibition mode

The final step in the biosynthesis of l-carnitine in humans is catalysed by the 2-oxoglutarate and ferrous iron dependent oxygenase, γ-butyrobetaine hydroxylase (BBOX). 1H and 19F NMR studies inform on the BBOX mechanism including by providing evidence for cooperativity between monomers in substrate...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2019-12, Vol.55 (98), p.14717-14720
Main Authors: Leśniak, Robert K, Rydzik, Anna M, Kamps, Jos J A G, Kahn, Amjad, Claridge, Timothy D W, Schofield, Christopher J
Format: Article
Language:English
Subjects:
Betaine - analogs & derivatives
Betaine - chemical synthesis
Betaine - chemistry
Betaine - metabolism
Carnitine - biosynthesis
Carnitine - chemical synthesis
Carnitine - chemistry
Carnitine - metabolism
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Fluorine - chemistry
gamma-Butyrobetaine Dioxygenase - antagonists & inhibitors
gamma-Butyrobetaine Dioxygenase - metabolism
Magnetic Resonance Spectroscopy
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Summary:The final step in the biosynthesis of l-carnitine in humans is catalysed by the 2-oxoglutarate and ferrous iron dependent oxygenase, γ-butyrobetaine hydroxylase (BBOX). 1H and 19F NMR studies inform on the BBOX mechanism including by providing evidence for cooperativity between monomers in substrate/some inhibitor binding. The value of the 19F NMR methods is demonstrated by their use in the design of new BBOX inhibitors.
ISSN:1359-7345
1364-548X
DOI:10.1039/c9cc06466d