TY - JOUR
T1 - Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules
AU - Ma, Bowen
AU - Khan, Khadija Shahed
AU - Xu, Tongyang
AU - Xeque Amada, Josefina
AU - Guo, Zhihao
AU - Huang, Yunpeng
AU - Yan, Yu
AU - Lam, Henry
AU - Cheng, Alfred Sze Lok
AU - Ng, Billy Wai Lung
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/4/10
Y1 - 2024/4/10
N2 - Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.
AB - Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12F36V-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.
UR - https://www.webofscience.com/wos/woscc/full-record/WOS:001195949600001
UR - https://openalex.org/W4393436827
UR - https://www.scopus.com/pages/publications/85189244761
U2 - 10.1021/jacs.3c14380
DO - 10.1021/jacs.3c14380
M3 - Journal Article
C2 - 38561350
SN - 0002-7863
VL - 146
SP - 9779
EP - 9789
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 14
ER -
