Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase.

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He Y, Martinez-Fleites C, Bubb A, Gloster TM, Davies GJ

Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase.

Carbohydr Res. 2009 Mar 31;344(5):627-31. doi: 10.1016/j.carres.2008.12.007. Epub 2008 Dec 13.

PubMed ID

19217614 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Streptozocin	O-GlcNAcase BT_4395	Protein	Bacteroides thetaiotaomicron (strain ATCC 29148 / DSM 2079 / NCTC 10582 / E50 / VPI-5482)	Yes	Antagonist	Details