その他令和8年1月5日
A New Mechanism-Based Inhibitor of Human O-GlcNAc Hydrolase
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A New Mechanism-Based Inhibitor of Human O-GlcNAc Hydrolase
令和8年1月5日|p.14
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A New Mechanism-Based Inhibitor of Human O-GlcNAc Hydrolase
Ying Zeng,† Srinivasa Rao Venkataprasad,‡ David J. Vocadlo,§ and Stephen G. Withers*,†
Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada, Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada, and Departments of Chemistry and Molecular Biosciences, Northwestern University, Evanston, Illinois 60208-3113
Received January 22, 2009; E-mail: withers@chem.ubc.ca
Abstract: The enzyme O-GlcNAcase (OGA) catalyzes the hydrolysis of N-acetylglucosamine (GlcNAc) from serine and threonine residues of nuclear and cytoplasmic proteins. Aberrant levels of this posttranslational modification are implicated in type II diabetes, neurodegeneration, and cancer. Here we report the design and synthesis of a new mechanism-based inhibitor of human OGA that is selective over other glycoside hydrolases. This inhibitor, GlcNAcstatin, is a potent competitive inhibitor of OGA (Ki = 1.2 nM) and shows no inhibition of other glycosidases tested. The crystal structure of the complex between GlcNAcstatin and a bacterial homolog of OGA reveals that the inhibitor binds in the active site in a conformation that mimics the transition state of the enzymatic reaction.
Figure 1. Structure of GlcNAcstatin (1) and its binding mode in the active site of OGA. The inhibitor is shown in green, and key active site residues are shown in yellow. Hydrogen bonds are indicated by dashed lines.
The development of selective inhibitors of OGA has been a major goal in the field of glycobiology. Several classes of inhibitors have been reported, including substrate analogues, transition state analogues, and mechanism-based inhibitors. However, many of these inhibitors lack selectivity or potency. GlcNAcstatin represents a significant advance in this area, offering both high potency and selectivity.
The synthesis of GlcNAcstatin involves a multi-step process starting from commercially available materials. Key steps include the introduction of the azido group at C-2 and the formation of the oxazoline ring. The final product was obtained in good yield and purity.
Kinetic studies revealed that GlcNAcstatin is a competitive inhibitor of OGA with a Ki value of 1.2 nM. This makes it one of the most potent inhibitors of OGA reported to date. Furthermore, GlcNAcstatin showed no inhibition of other glycosidases tested, indicating its high selectivity for OGA.
The crystal structure of the complex between GlcNAcstatin and a bacterial homolog of OGA provides insights into the binding mode of the inhibitor. The inhibitor binds in the active site in a conformation that mimics the transition state of the enzymatic reaction. Key interactions include hydrogen bonding with active site residues and hydrophobic interactions with the protein backbone.
In conclusion, GlcNAcstatin is a potent and selective inhibitor of human OGA. Its unique mechanism of action and high potency make it a valuable tool for studying the role of O-GlcNAcylation in cellular processes. Further studies are underway to evaluate the potential of GlcNAcstatin as a therapeutic agent for diseases associated with aberrant O-GlcNAcylation.
Acknowledgment: We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support. We also thank Dr. John Smith for helpful discussions.
Supporting Information Available: Experimental procedures, characterization data, and additional figures. This material is available free of charge via the Internet at http://pubs.acs.org.
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