Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase
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 biosynthe...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2014
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| _version_ | 1797066830905344000 |
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| author | Rydzik, A Chowdhury, R Kochan, G Williams, S McDonough, M Kawamura, A Schofield, C |
| author_facet | Rydzik, A Chowdhury, R Kochan, G Williams, S McDonough, M Kawamura, A Schofield, C |
| author_sort | Rydzik, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:47:38Z |
| format | Journal article |
| id | oxford-uuid:4a23ac67-a03d-4bb0-b89c-19977572432b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:47:38Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:4a23ac67-a03d-4bb0-b89c-19977572432b2022-03-26T15:35:49ZModulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4a23ac67-a03d-4bb0-b89c-19977572432bEnglishSymplectic Elements at Oxford2014Rydzik, AChowdhury, RKochan, GWilliams, SMcDonough, MKawamura, ASchofield, CCarnitine 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. |
| spellingShingle | Rydzik, A Chowdhury, R Kochan, G Williams, S McDonough, M Kawamura, A Schofield, C Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title | Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title_full | Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title_fullStr | Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title_full_unstemmed | Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title_short | Modulating carnitine levels by targeting its biosynthesis - selective inhibition of gamma-butyrobetaine hydroxylase |
| title_sort | modulating carnitine levels by targeting its biosynthesis selective inhibition of gamma butyrobetaine hydroxylase |
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