title: Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase.
abstract: Despite decades of its use in diabetes research, the mechanism of cytotoxicity of streptozotocin (STZ) toward pancreatic beta-islet cells has remained a topic of discussion. Although STZ toxicity is likely a function of its capacity to promote DNA alkylation, it has been proposed that STZ induces pancreatic beta-cell death through O-GlcNAcase inhibition. In this report, we explore the binding mode of STZ to a close homolog of human O-GlcNAcase, BtGH84 from Bacteroides thetaiotaomicron. Our results show that STZ binds in the enzyme active site in its intact form, without the formation of a covalent adduct, consistent with solution studies on BtGH84 and human O-GlcNAcase, as well as with structural work on a homolog from Clostridium perfringens. The active site of the BtGH84 is considerably deformed upon STZ binding and as a result the catalytic machinery is expelled from the binding cavity.
authors.affiliation: Department of Chemistry, Structural Biology Laboratory, The University of York, Heslington, York, YO10 5YW, UK.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.forename: Carlos
authors.initials: C
authors.lastname: Martinez-Fleites
authors.forename: Abigail
authors.initials: A
authors.lastname: Bubb
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Gloster
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
mesh_terms: D000118:Acetylglucosaminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001439:Bacteroides / Q000201:enzymology; D002151:Calorimetry; D003016:Clostridium perfringens / Q000201:enzymology; D018360:Crystallography, X-Ray / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013311:Streptozocin / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013311:Streptozocin; D000118:Acetylglucosaminidase