Streptozotocin inhibits O-GlcNAcase via the production of a transition state analog

Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase

“…9,17 In one of these mechanisms, it is argued that STZ decomposes to form a 'transition state analog' after the loss of nitric oxide and the release of the methyl group in STZ. Here, as with the previous work on NagJ, unambiguous electron density reveals an intact and well-ordered molecule of STZ in the active site.…”

“…16 The crystal structure of the BtGH84 enzyme in complex with STZ reveals an intact STZ molecule in the active site bound in a similar manner to that seen in a Clostridium perfringens homolog, 15 and confirms that there is neither STZ-induced covalent modification nor conversion of STZ into a potent transition state analog. 17 Intriguingly, STZ binding is also accompanied by a conformational change that flips the catalytic apparatus out of the active center reminiscent of the 'open' and 'closed' forms of the Clostridial NagJ enzyme, 18 but which had not previously been observed with BtGH84.…”

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…While widely used, recent evidence demonstrates that PUGNAc can also inhibit other lysosomal glycosidases including HexA and HexB (Macauley et al 2005;Ficko-Blean et al 2008), suggesting that PUGNAc may have effects on other cellular pathways aside from O-GlcNAcylation. STZ has also been widely used, but only inhibits O-GlcNAcase at very high concentrations (Toleman et al 2006;Gao et al 2000;Liu et al 2002;Okuyama and Yachi 2001;Roos et al 1998). It is important to note that STZ is also a DNAalkylating agent and can release nitric oxide, making it difficult to determine whether the observed effects are due to O-GlcNAcase inhibition or STZ toxicity (Kwon et al 1994).…”

Metabolic Control of Proteasome Function

“…Increased O-GlcNAc, the endogenous inhibitor of proteasome (85), has been shown to induce apoptosis. Glucosamine and/or STZ treatment, an O-GlcNAcase inhibitor (66,79) that causes the accumulation of O-GlcNAc, caused the accumulation of p53 and apoptosis in ␤-cells (45) and hippocampal pyramidal neurons as well (46), suggesting a role of O-GlcNAc inhibition of proteasome in ␤-cell failure and Alzheimer's. Mutant Rpt6S120A has been shown to act as a dominant negative and inhibits proteasome function in the living cell (84).…”