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The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants

Abstract:

Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins.

Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopenteny...

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Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1016/j.bone.2015.08.020

Authors


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Institution:
University of Oxford
Division:
MSD
Department:
NDORMS
Role:
Author
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Structural Genomics Consortium
Role:
Author
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDORMS
Role:
Author
More by this author
Institution:
University of Oxford
Division:
MSD
Department:
NDM
Sub department:
Structural Genomics Consortium
Role:
Author
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Oxford NIHR Biomedical Research Unit More from this funder
Medical Research Council More from this funder
Rosetrees Trust More from this funder
Biotechnology and Biological Sciences Research Council More from this funder
Publisher:
Elsevier Publisher's website
Journal:
Bone Journal website
Volume:
81
Pages:
478–486
Publication date:
2015-08-28
Acceptance date:
2015-08-23
DOI:
ISSN:
8756-3282
Language:
English
Keywords:
UUID:
uuid:3ef4e8d0-4bc8-4280-a1d0-2cf9e6a81b1c
Deposit date:
2015-11-11

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