Download MendeleyModulating carnitine levels by targeting its biosynthesis pathway - selective inhibition of gamma-butyrobetaine hydroxylase.
Rydzik, A.M., Chowdhury, R., Kochan, G.T., Williams, S.T., McDonough, M.A., Kawamura, A., Schofield, C.J.(2014) Chem Sci 5: 1765-1771
- PubMed: 26682037
- DOI: https://doi.org/10.1039/C4SC00020J
- Primary Citation of Related Structures:
4C8R - PubMed Abstract:
Carnitine is essential for fatty acid metabolism, but is associated with both health benefits and risks, especially heart diseases. 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.
Organizational Affiliation:
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
