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Lookup NU author(s): Professor Akane Kawamura
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Carnitine is essential for fatty acid metabolism, but is associated with both health benefits and risks, especially heart disease. We report the identification of potent, selective and cell active inhibitors of γ-butyrobetaine hydroxylase (BBOX), which catalyses the final step of carnitine biosynthesis in animals. A crystal structure of BBOX in complex with a lead inhibitor reveals that it binds in two modes, one of which adopts an unusual 'U-shape' conformation stabilised by inter- and intra-molecular π-stacking interactions. Conformational changes observed on binding of the inhibitor to BBOX likely reflect those occurring in catalysis; they also rationalise the inhibition of BBOX by high levels of its substrate γ-butyrobetaine (GBB), as observed both with isolated BBOX protein and in cellular studies. © 2014 the Partner Organisations.
Author(s): Rydzik AM, Chowdhury R, Kochan GT, Williams ST, McDonough MA, Kawamura A, Schofield CJ
Publication type: Article
Publication status: Published
Journal: Chemical Science
Print publication date: 01/05/2014
Online publication date: 11/02/2014
Acceptance date: 10/02/2014
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
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