Structural snapshots for mechanism-based inactivation of a glycoside          hydrolase by cyclopropyl carbasugars

Christopher Adamson; Robert J. Pengelly; Saeideh Shamsi Kazem Abadi; Saswati Chakladar; Jason Draper; Robert Britton; Tracey M. Gloster; Andrew J. Bennet

doi:10.1002/anie.201607431

Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl carbasugars

Christopher Adamson, Robert J. Pengelly, Saeideh Shamsi Kazem Abadi, Saswati Chakladar, Jason Draper, Robert Britton, Tracey M. Gloster, Andrew J. Bennet

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28 Citations (Scopus)

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Abstract

Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in ²H₃ conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened ²H₃ half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.

Original language	English
Pages (from-to)	14978-14982
Journal	Angewandte Chemie International Edition
Volume	55
Issue number	48
Early online date	26 Oct 2016
DOIs	https://doi.org/10.1002/anie.201607431
Publication status	Published - 18 Nov 2016

Keywords

Carbocycles
Enzyme mechanisms
Glycoside hydrolase
Inhibitors
X-ray crystallography

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10.1002/anie.201607431Licence: CC BY

Adamson_et_al-2016-Angewandte_Chemie_International_Edition
Copyright 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 2.49 MBLicence: CC BY

Tracey Gloster Fellowship: Understanding degradation of heparan sulphate with implications for disease
Gloster, T. (PI)
The Wellcome Trust
1/01/12 → 30/09/18
Project: Fellowship

Tracey Gloster
- tmgst-andrews.acuk
- School of Biology - Reader
- Biomedical Sciences Research Complex
Person: Academic

Cite this

@article{5582c897abae400fbcafeb2f41cf1062,

title = "Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl carbasugars",

abstract = "Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.",

keywords = "Carbocycles, Enzyme mechanisms, Glycoside hydrolase, Inhibitors, X-ray crystallography",

author = "Christopher Adamson and Pengelly, {Robert J.} and {Kazem Abadi}, {Saeideh Shamsi} and Saswati Chakladar and Jason Draper and Robert Britton and Gloster, {Tracey M.} and Bennet, {Andrew J.}",

note = "This work was supported by an NSERC Discovery Grant (AJB: #121348-2012), a Wellcome Trust Career Development Fellowship (TMG: grant 095828), a Wellcome Trust Institutional Strategic Support award (TMG and RJP), a MSFHR Career Investigator Award (RB), a NSERC Discovery Grant (RB), and an NSERC PGSM Scholarship (CA).",

year = "2016",

month = nov,

day = "18",

doi = "10.1002/anie.201607431",

language = "English",

volume = "55",

pages = "14978--14982",

journal = "Angewandte Chemie International Edition",

issn = "1433-7851",

publisher = "John Wiley & Sons, Ltd",

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TY - JOUR

T1 - Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl carbasugars

AU - Adamson, Christopher

AU - Pengelly, Robert J.

AU - Kazem Abadi, Saeideh Shamsi

AU - Chakladar, Saswati

AU - Draper, Jason

AU - Britton, Robert

AU - Gloster, Tracey M.

AU - Bennet, Andrew J.

N1 - This work was supported by an NSERC Discovery Grant (AJB: #121348-2012), a Wellcome Trust Career Development Fellowship (TMG: grant 095828), a Wellcome Trust Institutional Strategic Support award (TMG and RJP), a MSFHR Career Investigator Award (RB), a NSERC Discovery Grant (RB), and an NSERC PGSM Scholarship (CA).

PY - 2016/11/18

Y1 - 2016/11/18

N2 - Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.

AB - Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism-based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism-based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half-chair). We conclude that these inactivator reactions mainly involve motion of the pseudo-anomeric carbon atom, knowledge that should stimulate the design of new transition-state analogues for use as chemical biology tools.

KW - Carbocycles

KW - Enzyme mechanisms

KW - Glycoside hydrolase

KW - Inhibitors

KW - X-ray crystallography

U2 - 10.1002/anie.201607431

DO - 10.1002/anie.201607431

M3 - Article

SN - 1433-7851

VL - 55

SP - 14978

EP - 14982

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 48

ER -

Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl carbasugars

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Tracey Gloster Fellowship: Understanding degradation of heparan sulphate with implications for disease

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Tracey Gloster

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