2VUR

Chemical dissection of the link between Streptozotocin, O-GlcNAc and pancreatic cell death

Summary for 2VUR

• Entry DOI: 10.2210/pdb2vur/pdb
• Related: 2J62 2JH2 2V5C 2V5D
• Descriptor: O-GLCNACASE NAGJ, 2-deoxy-2-{[(2-hydroxy-1-methylhydrazino)carbonyl]amino}-beta-D-glucopyranose, SULFATE ION, ... (4 entities in total)
• Functional Keywords: hydrolase, streptozotocin (stz), o-glcnac hydrolase (oga), glycosidase
• Biological source: CLOSTRIDIUM PERFRINGENS
• Total number of polymer chains: 2
• Total formula weight: 134007.96

Authors

Pathak, S.,Dorfmueller, H.C.,Borodkin, V.S.,van Aalten, D.M.F. (deposition date: 2008-05-29, release date: 2009-02-10, Last modification date: 2024-05-08)

Primary citation

Pathak, S.,Dorfmueller, H.C.,Borodkin, V.S.,Van Aalten, D.M.F.
Chemical Dissection of the Link between Streptozotocin, O-Glcnac, and Pancreatic Cell Death.
Chem.Biol., 15:799-, 2008

PubMed Abstract: Streptozotocin is a natural product that selectively kills insulin-secreting beta cells, and is widely used to generate mouse models of diabetes or treat pancreatic tumors. Several studies suggest that streptozotocin toxicity stems from its N-nitrosourea moiety releasing nitric oxide and possessing DNA alkylating activity. However, it has also been proposed that streptozotocin induces apoptosis by inhibiting O-GlcNAcase, an enzyme that, together with O-GlcNAc transferase, is important for dynamic intracellular protein O-glycosylation. We have used galacto-streptozotocin to chemically dissect the link between O-GlcNAcase inhibition and apoptosis. Using X-ray crystallography, enzymology, and cell biological studies on an insulinoma cell line, we show that, whereas streptozotocin competitively inhibits O-GlcNAcase and induces apoptosis, its galacto-configured derivative no longer inhibits O-GlcNAcase, yet still induces apoptosis. This supports a general chemical poison mode of action for streptozotocin, suggesting the need for using more specific inhibitors to study protein O-GlcNAcylation.

PubMed: 18721751
DOI: 10.1016/J.CHEMBIOL.2008.06.010

Experimental method

X-RAY DIFFRACTION (2.2 Å)