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Synfacts 2022; 18(04): 0429
DOI: 10.1055/s-0041-1737943
Chemistry in Medicine and Biology

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

Autoren

    Rezensent(en):

  • Dirk Trauner

  • Klaus-Peter Ruehmann

González-Cuesta M, Sidhu P, Ashmus RA, Males A, Proceviat C, Madden Z, Rogalski JC, Busmann JA, Foster LJ, García Fernández JM, Davies GJ, *, Ortiz Mellet C, *, Vocadlo DJ. * University of York, UK; Universidad de Sevilla, Spain; Simon Fraser University, Burnaby, Canada
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
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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.




Publikationsverlauf

Artikel online veröffentlicht:
18. März 2022

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