Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase.
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.
He
Yuan
Y
Department of Chemistry, Structural Biology Laboratory, The University of York, Heslington, York, YO10 5YW, UK.
Martinez-Fleites
Carlos
C
Bubb
Abigail
A
Gloster
Tracey M
TM
Davies
Gideon J
GJ
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*
D004791:Enzyme Inhibitors; D013311:Streptozocin; D000118:Acetylglucosaminidase