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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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Publication details

The article was received on 03 Jan 2014, accepted on 10 Feb 2014 and first published on 11 Feb 2014


Article type: Edge Article
DOI: 10.1039/C4SC00020J
Author version available: Download Author version (PDF)
Citation: Chem. Sci., 2014,5, 1765-1771
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    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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