Journal
CHEMICAL SCIENCE
Volume 5, Issue 5, Pages 1765-1771Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4sc00020j
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Wellcome Trust
- European Union
- BHF Centre of Research Excellence, Oxford
- Dulverton Trust
- Biotechnology and Biological Sciences Research Council [BB/L000121/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/L003376/1] Funding Source: researchfish
- BBSRC [BB/L000121/1] Funding Source: UKRI
- EPSRC [EP/L003376/1] Funding Source: UKRI
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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 gamma-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 pi-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 gamma-butyrobetaine (GBB), as observed both with isolated BBOX protein and in cellular studies.
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