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

Lookup NU author(s): Professor Akane Kawamura

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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. © 2014 the Partner Organisations.

Publication metadata

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

Year: 2014

Volume: 5

Issue: 5

Pages: 1765-1771

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

URL: https://doi.org/10.1039/C4SC00020J

DOI: 10.1039/c4sc00020j

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