Research output: Contribution to journal › Article › peer-review
Journal | CARBOHYDRATE RESEARCH |
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Date | Published - 31 Mar 2009 |
Issue number | 5 |
Volume | 344 |
Number of pages | 5 |
Pages (from-to) | 627-631 |
Original language | English |
Despite decades of its use in diabetes research, the mechanism of cytotoxicity of streptozotocin (STZ) toward pancreatic P-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 p-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. (C) 2008 Elsevier Ltd. All rights reserved.
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