A Novel Thiazolidine Scaffold that Inhibits O-GlcNAcase (OGA)

Key words

OGA-inhibitors - chemoproteomic mapping - O-linked N-acetylglucosamine - Staudinger reduction - biotin

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.

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.

Publication History

Article published online:
18 March 2022