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Issue 5, 2014
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Modulating carnitine levels by targeting its biosynthesis – selective inhibition of γ-butyrobetaine hydroxylase

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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.

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

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Supplementary files

Article information


Submitted
03 Jan 2014
Accepted
10 Feb 2014
First published
11 Feb 2014

Chem. Sci., 2014,5, 1765-1771
Article type
Edge Article
Author version available

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

A. M. Rydzik, R. Chowdhury, G. T. Kochan, S. T. Williams, M. A. McDonough, A. Kawamura and C. J. Schofield, Chem. Sci., 2014, 5, 1765
DOI: 10.1039/C4SC00020J

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