Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 627-631 |
| Number of pages | 5 |
| Journal | CARBOHYDRATE RESEARCH |
| Volume | 344 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 31 Mar 2009 |
Keywords
- Streptozotocin
- O-GlcNAc
- Diabetes
- Inhibitor
- 3-D structure
- Carbohydrate-active enzyme
- BETA-CELL DEATH
- N-ACETYLGLUCOSAMINE
- DIABETOGENIC ACTION
- PROTEINS
- GLUCOSAMINIDASE
- BLOCKS
- ANALOG
- MIN6
- DNA