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Modulating carnitine levels by targeting its biosynthesis – selective inhibition of γ-butyrobetaine hydroxylase

DOI: 10.1039/c4sc00020j DOI Help

Authors: Anna M. Rydzik (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford) , Grazyna T. Kochan (Structural Genomics Consortium, University of Oxford) , Sophie T. Williams (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Akane Kawamura (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 5 , PAGES 1765-1771

State: Published (Approved)
Published: February 2014

Abstract: 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.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography