hsp90 is required for heme binding and activation of apo-neuronal nitric-oxide synthase: geldanamycin-mediated oxidant generation is unrelated to any action of hsp90

The Journal of Biological Chemistry
Scott S BilleckeYoichi Osawa

Abstract

It is established that neuronal NO synthase (nNOS) is associated with the chaperone hsp90, although the functional role for this interaction has not been defined. We have discovered that inhibition of hsp90 by radicicol or geldanamycin nearly prevents the heme-mediated activation and assembly of heme-deficient apo-nNOS in insect cells. This effect is concentration-dependent with over 75% inhibition achieved at 20 microm radicicol. The ferrous carbonyl complex of nNOS is not formed when hsp90 is inhibited, indicating that functional heme insertion is prevented. We propose that the hsp90-based chaperone machinery facilitates functional heme entry into apo-nNOS by the opening of the hydrophobic heme-binding cleft in the protein. Previously, it has been reported that the hsp90 inhibitor geldanamycin uncouples endothelial NOS activity and increases endothelial NOS-dependent O(2)() production. Geldanamycin is an ansamycin benzoquinone, and we show here that it causes oxidant production from nNOS in insect cells as well as with the purified protein. At a concentration of 20 microm, geldanamycin causes a 3-fold increase in NADPH oxidation and hydrogen peroxide formation from purified nNOS, whereas the non-quinone hsp90 inhibitor radici...Continue Reading

References

Dec 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·K McMillanB S Masters
Nov 1, 1989·Archives of Biochemistry and Biophysics·A AsseffaF J Gonzalez
Aug 29, 1995·Proceedings of the National Academy of Sciences of the United States of America·L J RomanB S Masters
Aug 30, 1994·Proceedings of the National Academy of Sciences of the United States of America·L WhitesellL M Neckers
Feb 4, 1997·Proceedings of the National Academy of Sciences of the United States of America·K SugiyamaY Osawa
May 15, 1998·Nature·G García-CardeñaW C Sessa
Jan 9, 1999·The Journal of Biological Chemistry·A T BenderY Osawa
Sep 10, 1999·The Journal of Biological Chemistry·J Vásquez-VivarB Kalyanaraman
Apr 7, 2000·The Journal of Biological Chemistry·A T BenderY Osawa
Aug 22, 2000·The Journal of Biological Chemistry·A T BenderY Osawa
Nov 8, 2001·American Journal of Physiology. Cell Physiology·Y SongY Xia

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Citations

Dec 17, 2009·Pflügers Archiv : European journal of physiology·Ingrid Fleming
Aug 27, 2005·Mitochondrion·Paul S Brookes
Mar 20, 2004·Pharmacology & Therapeutics·Amere Subbarao Sreedhar, Peter Csermely
Feb 1, 2003·Trends in Pharmacological Sciences·Giuseppe CirinoWilliam C Sessa
Jun 3, 2008·The Journal of Biological Chemistry·William B PrattYoichi Osawa
Apr 17, 2010·World Journal of Gastroenterology : WJG·Lukas MoledaReiner Wiest
Jan 1, 2010·Cell Stress & Chaperones·Virginia L VegaAntonio De Maio
Oct 13, 2015·Free Radical Biology & Medicine·Feng ChenDavid J R Fulton
Jul 1, 2008·The European Journal of Neuroscience·John Garthwaite
Oct 21, 2006·Vascular Pharmacology·Gunay Yetik-Anacak, John D Catravas
Jan 7, 2014·Biochimica Et Biophysica Acta·Alejandra G ErlejmanMario D Galigniana
May 18, 2016·Pflügers Archiv : European journal of physiology·Mauro Siragusa, Ingrid Fleming
Jan 30, 2007·Ecotoxicology and Environmental Safety·Nolan OsborneSuzanne Currie
Oct 29, 2004·The Journal of Biological Chemistry·Nataliya BalashovaAnnie Beuve
Apr 3, 2003·Nature Reviews. Genetics·Suzanne L Rutherford
Mar 6, 2007·American Journal of Physiology. Lung Cellular and Molecular Physiology·Judy L AschnerCandice D Fike
Mar 4, 2006·The Journal of Pharmacology and Experimental Therapeutics·Aparajita Dey, Arthur I Cederbaum
Jan 23, 2003·The Journal of Pharmacology and Experimental Therapeutics·Yoichi OsawaScott S Billecke
Dec 17, 2002·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Ingrid Fleming, Rudi Busse
May 25, 2004·The Journal of Biological Chemistry·Scott S BilleckeYoichi Osawa
Mar 9, 2004·The Journal of Biological Chemistry·Mario D GalignianaWilliam B Pratt
Oct 11, 2003·American Journal of Physiology. Heart and Circulatory Physiology·Jingsong OuKirkwood A Pritchard
Jan 23, 2020·International Journal of Molecular Sciences·Magdalena Gorska-PonikowskaFrancesco Cappello
Oct 3, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Wensheng LangJohn A Masucci
Feb 4, 2003·Experimental Biology and Medicine·William B Pratt, David O Toft
Nov 20, 2015·Frontiers in Physiology·Boris S ShenkmanYulia N Lomonosova
Jul 12, 2003·The Journal of Biological Chemistry·Masako Yoshida, Yong Xia
Mar 1, 2018·The Journal of Experimental Biology·Xiao-Xue YangPei-Yuan Qian
Nov 1, 2018·Physiological Reviews·Jesús TejeroMark T Gladwin

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