Unknown

Dataset Information

0

Modulating carnitine levels by targeting its biosynthesis pathway - selective inhibition of ?-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 ?-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 ?-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 ?-butyrobetaine (GBB), as observed both with isolated BBOX protein and in cellular studies.

SUBMITTER: Rydzik AM 

PROVIDER: S-EPMC4678601 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Rydzik Anna M AM   Chowdhury Rasheduzzaman R   Kochan Grazyna T GT   Williams Sophie T ST   McDonough Michael A MA   Kawamura Akane A   Schofield Christopher J CJ  

Chemical science 20140501 5


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-m  ...[more]

Similar Datasets

| S-EPMC4337704 | biostudies-literature
| S-EPMC6927413 | biostudies-literature
| S-EPMC4736438 | biostudies-literature
| S-EPMC8364193 | biostudies-literature
| S-EPMC1144272 | biostudies-other
| S-EPMC3442516 | biostudies-literature
| S-EPMC4255476 | biostudies-literature
2021-02-03 | GSE165976 | GEO
| S-EPMC4798942 | biostudies-literature
2009-02-18 | GSE10677 | GEO