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

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)799-807
    Number of pages9
    JournalChemistry & Biology
    Volume15
    Issue number8
    DOIs
    Publication statusPublished - 25 Aug 2008

    Keywords

    • beta-D-glucosaminidase
    • N-acetylglucosamine
    • Cytoplasmic proteins
    • Structural insights
    • Nitric oxide
    • Inhibitor
    • Glycosylation
    • Transferase
    • Alloxan
    • Nuclear

    Cite this