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DOI: 10.1055/s-0041-1737943
A Novel Thiazolidine Scaffold that Inhibits O-GlcNAcase (OGA)
Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-Translational Modifications.
J. Am. Chem. Soc. 2022;
144: 832-844
DOI: 10.1021/jacs.1c10504.
Key words
OGA-inhibitors - chemoproteomic mapping - O-linked N-acetylglucosamine - Staudinger reduction - biotin![](https://www.thieme-connect.de/media/synfacts/202204/i_t045_s1_10-1055_s-0041-1737943.gif)
Significance
O-Linked N-acetylglucosamine (O-GlcNAc) is an important post-translational modification (PTM) that regulates many cellular processes. In contrast to numerous kinases and phosphatases controlling the phosphorylation state of the proteome, only two enzymes are responsible for O-GlcNAc installation (O-GlcNAc transferase, OGT) and removal (O-GlcNAcase, OGA). The regulation of OGA activity remains poorly understood despite a dysregulation being linked to various neurodegenerative diseases.
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Comment
The authors developed a novel series of OGA inhibitors with picomolar binding affinity that are based on the aminosugar dideoxynojirimycin. Structural mimicry of the hydrolyzing transition state guided the search toward the bicyclic imino-thiazolidine scaffold. Furthermore, a biotin-conjugate was synthesized, which served as an affinity-purification tag and revealed new PTMs of OGA from brain cell tissue lysates. Both inhibitors and probes could serve as important tools to elucidate the regulatory mechanism of OGA.
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Publication History
Article published online:
18 March 2022
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