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

Chemistry & Biology
Shalini PathakDaan M F van Aalten

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.

References

Jan 1, 1968·Molecular & General Genetics : MGG·T GichnerJ Krepinský
Oct 1, 1983·Proceedings of the National Academy of Sciences of the United States of America·R C DukeJ J Cohen
Feb 1, 1982·Journal of Medicinal Chemistry·J MartinezF Winternitz
Dec 30, 1993·Biochemical and Biophysical Research Communications·J TurkM L McDaniel
Jan 26, 1999·Archives of Biochemistry and Biophysics·J A HanoverS M Sato
Mar 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·K LiuJ E Kudlow
Jul 19, 2001·The Surgical Clinics of North America·R Brentjens, L Saltz
Sep 14, 2001·Biochemical and Biophysical Research Communications·R Okuyama, M Yachi
Dec 5, 2002·Mutation Research·Alejandro D Bolzán, Martha S Bianchi
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 27, 2005·Biochemical and Biophysical Research Communications·Clifford TolemanJeffrey E Kudlow
Mar 3, 2006·The Journal of Biological Chemistry·Peiqi HuDavid S Rubenstein
Mar 17, 2006·The EMBO Journal·Francesco V RaoDaan M F van Aalten
Jun 20, 2006·Biochimica Et Biophysica Acta·Natasha E Zachara, Gerald W Hart
Oct 19, 2006·Biochemical and Biophysical Research Communications·Thomas N LeeRobert J Konrad
Dec 21, 2006·Journal of the American Chemical Society·Helge C DorfmuellerDaan M F van Aalten
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Mar 19, 2009·World Journal of Gastroenterology : WJG·Wen-Peng YuanXue-Kui Xia
Dec 23, 2009·FEBS Letters·Helge C Dorfmueller, Daan M F van Aalten
Nov 16, 2010·Diabetes & Metabolism·T IssadP Pagesy
Apr 23, 2010·Journal of the American Society of Hypertension : JASH·Victor V LimaRita C Tostes
Aug 12, 2009·Biochimica Et Biophysica Acta·Matthew S Macauley, David J Vocadlo
Aug 4, 2009·Biochimica Et Biophysica Acta·John A HanoverDona C Love
Aug 4, 2009·Biochimica Et Biophysica Acta·Carlos Martinez-FleitesGideon J Davies
Mar 12, 2009·The Biochemical Journal·Helge C DorfmuellerDaan M F van Aalten
Sep 25, 2010·The Biochemical Journal·Marianne SchimplDaan M F van Aalten
Oct 26, 2013·The Biochemical Journal·Adam Ostrowski, Daan M F van Aalten
Sep 30, 2008·Current Opinion in Structural Biology·Ramon Hurtado-GuerreroDaan M F van Aalten
Jan 6, 2017·ACS Chemical Biology·Matthew WorthJiaoyang Jiang
Nov 13, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ghadeer A R Y SuaifanVincenzo Abbate
Mar 27, 2010·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Enrico CrivellatoDomenico Ribatti
May 24, 2018·Journal of Bioenergetics and Biomembranes·Olof Lagerlöf
Jan 9, 2021·Chemical Reviews·Junfeng MaGerald W Hart

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Methods Mentioned

BETA
NMR
X-ray
fluorescence-assisted cell sorting
protein assay
FACS
flow cytometry

Software Mentioned

Openlab ( Improvision
HKL
GraFit
Coot
REFMAC

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