Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont

Yanping Zhu; Michael D. L. Suits; Andrew J. Thompson; Sambhaji Chavan; Zoran Dinev; Claire Dumon; Nicola Smith; Kelley W. Moremen; Yong Xiang; Aloysius Siriwardena; Spencer J. Williams; Harry J. Gilbert; Gideon J. Davies

doi:10.1038/NCHEMBIO.278

Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont

Yanping Zhu, Michael D. L. Suits, Andrew J. Thompson, Sambhaji Chavan, Zoran Dinev, Claire Dumon, Nicola Smith, Kelley W. Moremen, Yong Xiang, Aloysius Siriwardena, Spencer J. Williams, Harry J. Gilbert, Gideon J. Davies

Chemistry

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

Abstract

Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are alpha-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state C-4(1) chair conformation toward the transition state.

Original language	English
Pages (from-to)	125-132
Number of pages	8
Journal	NATURE CHEMICAL BIOLOGY
Volume	6
Issue number	2
DOIs	https://doi.org/10.1038/NCHEMBIO.278
Publication status	Published - Feb 2010

Keywords

PUTATIVE CATALYTIC RESIDUES
HUMAN INTESTINE
BACTEROIDES-THETAIOTAOMICRON
PSEUDOMONAS-CELLULOSA
TRANSITION-STATE
STRUCTURAL BASIS
MOLECULAR-BASIS
MICROBIOME
INHIBITION
MANNANASE

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10.1038/NCHEMBIO.278

Dissection of alpha mannosidases from reaction corodinate to inhibition
Davies, G. J.
BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL)
16/11/09 → 30/09/13
Project: Research project (funded) › Research

Cite this

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title = "Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont",

abstract = "Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are alpha-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state C-4(1) chair conformation toward the transition state.",

keywords = "PUTATIVE CATALYTIC RESIDUES, HUMAN INTESTINE, BACTEROIDES-THETAIOTAOMICRON, PSEUDOMONAS-CELLULOSA, TRANSITION-STATE, STRUCTURAL BASIS, MOLECULAR-BASIS, MICROBIOME, INHIBITION, MANNANASE",

author = "Yanping Zhu and Suits, {Michael D. L.} and Thompson, {Andrew J.} and Sambhaji Chavan and Zoran Dinev and Claire Dumon and Nicola Smith and Moremen, {Kelley W.} and Yong Xiang and Aloysius Siriwardena and Williams, {Spencer J.} and Gilbert, {Harry J.} and Davies, {Gideon J.}",

year = "2010",

month = feb,

doi = "10.1038/NCHEMBIO.278",

language = "English",

volume = "6",

pages = "125--132",

journal = "NATURE CHEMICAL BIOLOGY",

issn = "1552-4450",

publisher = "Nature Publishing Group",

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AU - Zhu, Yanping

AU - Suits, Michael D. L.

AU - Thompson, Andrew J.

AU - Chavan, Sambhaji

AU - Dinev, Zoran

AU - Dumon, Claire

AU - Smith, Nicola

AU - Moremen, Kelley W.

AU - Xiang, Yong

AU - Siriwardena, Aloysius

AU - Williams, Spencer J.

AU - Gilbert, Harry J.

AU - Davies, Gideon J.

PY - 2010/2

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N2 - Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are alpha-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state C-4(1) chair conformation toward the transition state.

AB - Colonic bacteria, exemplified by Bacteroides thetaiotaomicron, play a key role in maintaining human health by harnessing large families of glycoside hydrolases (GHs) to exploit dietary polysaccharides and host glycans as nutrients. Such GH family expansion is exemplified by the 23 family GH92 glycosidases encoded by the B. thetaiotaomicron genome. Here we show that these are alpha-mannosidases that act via a single displacement mechanism to utilize host N-glycans. The three-dimensional structure of two GH92 mannosidases defines a family of two-domain proteins in which the catalytic center is located at the domain interface, providing acid (glutamate) and base (aspartate) assistance to hydrolysis in a Ca2+-dependent manner. The three-dimensional structures of the GH92s in complex with inhibitors provide insight into the specificity, mechanism and conformational itinerary of catalysis. Ca2+ plays a key catalytic role in helping distort the mannoside away from its ground-state C-4(1) chair conformation toward the transition state.

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KW - BACTEROIDES-THETAIOTAOMICRON

KW - PSEUDOMONAS-CELLULOSA

KW - TRANSITION-STATE

KW - STRUCTURAL BASIS

KW - MOLECULAR-BASIS

KW - MICROBIOME

KW - INHIBITION

KW - MANNANASE

U2 - 10.1038/NCHEMBIO.278

DO - 10.1038/NCHEMBIO.278

M3 - Article

SN - 1552-4450

VL - 6

SP - 125

EP - 132

JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 2

ER -

Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont

Abstract

Keywords

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Projects

Dissection of alpha mannosidases from reaction corodinate to inhibition

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