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

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Pathak S, Dorfmueller HC, Borodkin VS, van Aalten DM

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

Chem Biol. 2008 Aug 25;15(8):799-807. doi: 10.1016/j.chembiol.2008.06.010.

PubMed ID

18721751 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Streptozocin	Bifunctional protein NCOAT	Protein	Humans	Unknown	Not Available	Details