Inhibition of P-glycoprotein ATPase activity by beryllium fluoride

Biochemistry
B SankaranA E Senior

Abstract

ATPase activity of P-glycoprotein (multidrug-resistance protein) was found to be potently inhibited by beryllium fluoride (BeFx) in combination with MgATP, MgADP, or corresponding Mg-8-azido-nucleotides. Inhibition was due to trapping of nucleoside diphosphate at catalytic sites. Full inhibition was achieved on trapping of 1 mol of nucleotide per mol of Pgp. Reactivation was slow (t(1/2) = 32 min at 37 degrees C), and release of trapped nucleotide correlated with recovery of ATPase. Trapping of 8-azido-ADP followed by UV irradiation yielded permanent inactivation and specific labeling of Pgp in plasma membranes. Both N- and C-terminal nucleotide binding sites were labeled. These findings give strong confirmation of the concepts that in intact Pgp both nucleotide sites are active in MgATP hydrolysis, and that they interact strongly. The characteristics of inhibition by BeFx were similar in general to those seen with vanadate. However, PPi gave strong protection against BeFx inhibition, and in this respect, inhibition by BeFx was clearly different from vanadate inhibition.

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Citations

May 13, 2006·Journal of Bioenergetics and Biomembranes·Gregory Tombline, Alan E Senior
May 3, 2003·Journal of Experimental Therapeutics & Oncology·John A Kellen
Jun 6, 2002·European Journal of Biochemistry·Katalin GodaGábor Szabó
Oct 23, 2012·Cancer Research·Ekaterina V MalofeevaElizabeth A Hopper-Borge
Jul 13, 2000·Biochemical and Biophysical Research Communications·A KernA Váradi
Oct 12, 2000·Biochemical and Biophysical Research Communications·G SzakácsA Váradi
Mar 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·Z E Sauna, S V Ambudkar
Feb 22, 2012·The Journal of Physical Chemistry. B·Jean-François St-PierreNormand Mousseau
Jan 13, 2009·Biochimica Et Biophysica Acta·Markus A Seeger, Hendrik W van Veen
Jun 15, 2007·The FEBS Journal·Heidi de WetFrances M Ashcroft
Feb 28, 2006·The Journal of Biological Chemistry·Kei TakahashiKazumitsu Ueda
Jul 27, 2006·The Journal of Biological Chemistry·Jin WangXiao-Song Xie
Nov 26, 2003·The Journal of Biological Chemistry·Gregory TomblineAlan E Senior
Oct 25, 2003·Oncogene·Suresh V AmbudkarMichael M Gottesman
Aug 25, 2004·The Journal of Biological Chemistry·Gregory TomblineAlan E Senior
Jul 14, 2001·The Journal of Biological Chemistry·Z E SaunaS V Ambudkar
Apr 20, 2002·The Journal of Biological Chemistry·Tongqing ZhouBarry P Rosen
Dec 15, 2005·The Journal of Biological Chemistry·Da-Wei ZhangHelen H Hobbs

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