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

Bone
Maria K TsoumpraJames E Dunford

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 Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unkno...Continue Reading

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Citations

Jan 20, 2016·Expert Opinion on Drug Discovery·Juan B RodriguezSergio H Szajnman
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Jul 28, 2019·The FEBS Journal·Liang GuMandeep Kaur
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Apr 27, 2021·PloS One·Paola Ruiz PuentesPablo Arbeláez
Jun 8, 2021·BioMed Research International·Michele MirandaPatrizio Bollero

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Methods Mentioned

BETA
GTPase
X-ray

Software Mentioned

REFMAC5
PHASER
MOSFLM
Graphpad Prism
SCALA
COOT
Graphpad Prism®

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