Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

Andrew J. Thompson; Gaetano Speciale; Javier Iglesias-Fernández; Zalihe Hakki; Tyson Belz; Alan Cartmell; Richard J. Spears; Emily Chandler; Max J. Temple; Judith Stepper; Harry J. Gilbert; Carme Rovira; Spencer J. Williams; Gideon J. Davies

doi:10.1002/anie.201410502

Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

Andrew J. Thompson, Gaetano Speciale, Javier Iglesias-Fernández, Zalihe Hakki, Tyson Belz, Alan Cartmell, Richard J. Spears, Emily Chandler, Max J. Temple, Judith Stepper, Harry J. Gilbert, Carme Rovira^*, Spencer J. Williams, Gideon J. Davies

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an ^OS₂ conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B_2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B_2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through ^OS₂ and B_2,5 ^≠ conformations, information that should inspire the development of new antifungal agents.

Original language	English
Pages (from-to)	5378-5382
Number of pages	5
Journal	Angewandte Chemie International Edition
Volume	54
Issue number	18
Early online date	13 Mar 2015
DOIs	https://doi.org/10.1002/anie.201410502
Publication status	Published - 27 Apr 2015

Bibliographical note

Keywords

Carbohydrates
Computational chemistry
Conformational analysis
Enzymatic mechanisms
Glycosidase inhibitors

Access to Document

10.1002/anie.201410502

Cite this

Thompson, A. J., Speciale, G., Iglesias-Fernández, J., Hakki, Z., Belz, T., Cartmell, A., Spears, R. J., Chandler, E., Temple, M. J., Stepper, J., Gilbert, H. J., Rovira, C., Williams, S. J., & Davies, G. J. (2015). Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism. Angewandte Chemie International Edition, 54(18), 5378-5382. https://doi.org/10.1002/anie.201410502

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title = "Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism",

abstract = "α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an OS2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through OS2 and B2,5 ≠ conformations, information that should inspire the development of new antifungal agents.",

keywords = "Carbohydrates, Computational chemistry, Conformational analysis, Enzymatic mechanisms, Glycosidase inhibitors",

author = "Thompson, {Andrew J.} and Gaetano Speciale and Javier Iglesias-Fern{\'a}ndez and Zalihe Hakki and Tyson Belz and Alan Cartmell and Spears, {Richard J.} and Emily Chandler and Temple, {Max J.} and Judith Stepper and Gilbert, {Harry J.} and Carme Rovira and Williams, {Spencer J.} and Davies, {Gideon J.}",

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doi = "10.1002/anie.201410502",

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Thompson, AJ, Speciale, G, Iglesias-Fernández, J, Hakki, Z, Belz, T, Cartmell, A, Spears, RJ, Chandler, E, Temple, MJ, Stepper, J, Gilbert, HJ, Rovira, C, Williams, SJ & Davies, GJ 2015, 'Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism', Angewandte Chemie International Edition, vol. 54, no. 18, pp. 5378-5382. https://doi.org/10.1002/anie.201410502

Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism. / Thompson, Andrew J.; Speciale, Gaetano; Iglesias-Fernández, Javier et al.
In: Angewandte Chemie International Edition, Vol. 54, No. 18, 27.04.2015, p. 5378-5382.

Research output: Contribution to journal › Article › peer-review

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AU - Thompson, Andrew J.

AU - Speciale, Gaetano

AU - Iglesias-Fernández, Javier

AU - Hakki, Zalihe

AU - Belz, Tyson

AU - Cartmell, Alan

AU - Spears, Richard J.

AU - Chandler, Emily

AU - Temple, Max J.

AU - Stepper, Judith

AU - Gilbert, Harry J.

AU - Rovira, Carme

AU - Williams, Spencer J.

AU - Davies, Gideon J.

PY - 2015/4/27

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N2 - α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an OS2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through OS2 and B2,5 ≠ conformations, information that should inspire the development of new antifungal agents.

AB - α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an OS2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through OS2 and B2,5 ≠ conformations, information that should inspire the development of new antifungal agents.

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KW - Computational chemistry

KW - Conformational analysis

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DO - 10.1002/anie.201410502

M3 - Article

C2 - 25772148

SN - 1433-7851

VL - 54

SP - 5378

EP - 5382

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 18

ER -

Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Gideon John Davies, FRS, FMedSci

Glycosylation: Programmes for Observation, Inhibition & Structure-based Exploitation of key carbohydrate-active enzymes

Dissection of alpha mannosidases from reaction corodinate to inhibition

Cite this

Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Profiles

Gideon John Davies, FRS, FMedSci

Projects

Glycosylation: Programmes for Observation, Inhibition & Structure-based Exploitation of key carbohydrate-active enzymes

Dissection of alpha mannosidases from reaction corodinate to inhibition

Cite this