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  • Title: Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase.
    Author: He Y, Martinez-Fleites C, Bubb A, Gloster TM, Davies GJ.
    Journal: Carbohydr Res; 2009 Mar 31; 344(5):627-31. PubMed ID: 19217614.
    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.
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