Structural and biochemical evidence for a boat-like transition state in beta-mannosidases

Louise E. Tailford; Wendy A. Offen; Nicola L. Smith; Claire Dumon; Carl Morland; Julie Gratien; Marie-Pierre Heck; Robert V. Stick; Yves Bleriot; Andrea Vasella; Harry J. Gilbert; Gideon J. Davies

doi:10.1038/nchembio.81

Structural and biochemical evidence for a boat-like transition state in beta-mannosidases

Louise E. Tailford, Wendy A. Offen, Nicola L. Smith, Claire Dumon, Carl Morland, Julie Gratien, Marie-Pierre Heck, Robert V. Stick, Yves Bleriot, Andrea Vasella, Harry J. Gilbert, Gideon J. Davies

Chemistry

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

Abstract

Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B-2,B-5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose K-i values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron b-mannosidase BtMan2A. B-2,B-5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log K-i with log K-m/K-cat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B-2,B-5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases-an area that is emerging for anticancer therapeutics.

Original language	English
Pages (from-to)	306-312
Number of pages	7
Journal	NATURE CHEMICAL BIOLOGY
Volume	4
Issue number	5
DOIs	https://doi.org/10.1038/nchembio.81
Publication status	Published - 23 May 2008

Keywords

DIFFERENT CONFORMATIONAL ITINERARIES
GLYCOSIDASE INHIBITORS
SUBSTRATE DISTORTION
ISOFAGOMINE LACTAM
ANALOG INHIBITORS
D-GLUCOSE
BINDING
MECHANISM
GLUCOSIDASES
AMIDINE

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http://www.nature.com/nchembio/journal/v4/n5/full/nchembio.81.html

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title = "Structural and biochemical evidence for a boat-like transition state in beta-mannosidases",

abstract = "Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B-2,B-5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose K-i values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron b-mannosidase BtMan2A. B-2,B-5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log K-i with log K-m/K-cat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B-2,B-5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases-an area that is emerging for anticancer therapeutics.",

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author = "Tailford, {Louise E.} and Offen, {Wendy A.} and Smith, {Nicola L.} and Claire Dumon and Carl Morland and Julie Gratien and Marie-Pierre Heck and Stick, {Robert V.} and Yves Bleriot and Andrea Vasella and Gilbert, {Harry J.} and Davies, {Gideon J.}",

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AU - Tailford, Louise E.

AU - Offen, Wendy A.

AU - Smith, Nicola L.

AU - Dumon, Claire

AU - Morland, Carl

AU - Gratien, Julie

AU - Heck, Marie-Pierre

AU - Stick, Robert V.

AU - Bleriot, Yves

AU - Vasella, Andrea

AU - Gilbert, Harry J.

AU - Davies, Gideon J.

PY - 2008/5/23

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N2 - Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B-2,B-5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose K-i values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron b-mannosidase BtMan2A. B-2,B-5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log K-i with log K-m/K-cat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B-2,B-5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases-an area that is emerging for anticancer therapeutics.

AB - Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B-2,B-5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose K-i values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron b-mannosidase BtMan2A. B-2,B-5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log K-i with log K-m/K-cat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B-2,B-5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases-an area that is emerging for anticancer therapeutics.

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KW - SUBSTRATE DISTORTION

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KW - ANALOG INHIBITORS

KW - D-GLUCOSE

KW - BINDING

KW - MECHANISM

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KW - AMIDINE

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JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 5

ER -

Structural and biochemical evidence for a boat-like transition state in beta-mannosidases

Abstract

Keywords

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