A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

Scott A. Yuzwa; Matthew S. Macauley; Julia E. Heinonen; Xiaoyang Shan; Rebecca J. Dennis; Yuan He; Garrett E. Whitworth; Keith A. Stubbs; Ernest J. McEachern; Gideon J. Davies; David J. Vocadlo

doi:10.1038/nchembio.96

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

Scott A. Yuzwa
, Matthew S. Macauley
, Julia E. Heinonen
, Xiaoyang Shan
, Rebecca J. Dennis
, Yuan He
, Garrett E. Whitworth
, Keith A. Stubbs
, Ernest J. McEachern
, Gideon J. Davies
, David J. Vocadlo

Chemistry

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

Abstract

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K-i = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

Original language	English
Pages (from-to)	483-490
Number of pages	8
Journal	NATURE CHEMICAL BIOLOGY
Volume	4
Issue number	8
DOIs	https://doi.org/10.1038/nchembio.96
Publication status	Published - Aug 2008

Keywords

BETA-N-ACETYLGLUCOSAMINIDASE
PAIRED HELICAL FILAMENTS
GLYCOGEN-SYNTHASE KINASE-3-BETA
SUBSTRATE-ASSISTED CATALYSIS
TETRATRICOPEPTIDE REPEATS
NEUROFIBRILLARY TANGLES
ALZHEIMERS-DISEASE
CYTOSOLIC PROTEINS
D-GLUCOSAMINIDASE
NAG-THIAZOLINE

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10.1038/nchembio.96

http://www.nature.com/nchembio/journal/v4/n8/full/nchembio.96.html

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title = "A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo",

abstract = "Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K-i = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.",

keywords = "BETA-N-ACETYLGLUCOSAMINIDASE, PAIRED HELICAL FILAMENTS, GLYCOGEN-SYNTHASE KINASE-3-BETA, SUBSTRATE-ASSISTED CATALYSIS, TETRATRICOPEPTIDE REPEATS, NEUROFIBRILLARY TANGLES, ALZHEIMERS-DISEASE, CYTOSOLIC PROTEINS, D-GLUCOSAMINIDASE, NAG-THIAZOLINE",

author = "Yuzwa, \{Scott A.\} and Macauley, \{Matthew S.\} and Heinonen, \{Julia E.\} and Xiaoyang Shan and Dennis, \{Rebecca J.\} and Yuan He and Whitworth, \{Garrett E.\} and Stubbs, \{Keith A.\} and McEachern, \{Ernest J.\} and Davies, \{Gideon J.\} and Vocadlo, \{David J.\}",

year = "2008",

month = aug,

doi = "10.1038/nchembio.96",

language = "English",

volume = "4",

pages = "483--490",

journal = "NATURE CHEMICAL BIOLOGY",

issn = "1552-4450",

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AU - Yuzwa, Scott A.

AU - Macauley, Matthew S.

AU - Heinonen, Julia E.

AU - Shan, Xiaoyang

AU - Dennis, Rebecca J.

AU - He, Yuan

AU - Whitworth, Garrett E.

AU - Stubbs, Keith A.

AU - McEachern, Ernest J.

AU - Davies, Gideon J.

AU - Vocadlo, David J.

PY - 2008/8

Y1 - 2008/8

N2 - Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K-i = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

AB - Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K-i = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.

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KW - TETRATRICOPEPTIDE REPEATS

KW - NEUROFIBRILLARY TANGLES

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JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 8

ER -

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

Abstract

Keywords

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