title: Modulating carnitine levels by targeting its biosynthesis pathway - selective inhibition of γ-butyrobetaine hydroxylase.
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.
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rydzik
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Rasheduzzaman
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Roosvelt Drive, Headington OX3 7DQ, United Kingdom.
authors.forename: Grazyna T
authors.initials: GT
authors.lastname: Kochan
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Sophie T
authors.initials: ST
authors.lastname: Williams
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. ; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield