Inhibition of the GDP/GTP exchange reaction of ras p21 by aluminum ion.
In an effort to understand the biochemical mechanisms of aluminum-induced neurotoxicity, we investigated the effects of aluminum ion, Al3+, on the Mg(2+)- and nucleotide-dependent protein, ras p21. Picomolar Al3+ concentrations inhibited the GTPase activity of ras p21 in an Mg(2+)-dependent manner, consistent with an Al3+/Mg2+ competition mechanism. GTPase activity was inhibited by 60% in the presence of 100 microM Mg2+ and 2.9 x 10(-10) M Al3+. Kinetic studies demonstrated that the mode of Al(3+)-induced inhibition of ras p21 GTPase activity changed from competitive to mixed non-competitive as the number of ras p21 turnovers increased. Further dissection of the ras p21 cycle revealed that Mg(2+)-dependent GDP/GTP exchange was the Al(3+)-sensitive step.
Landino
L M
LM
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Macdonald
T L
TL
D000535:Aluminum / Q000494:pharmacology*; D003001:Cloning, Molecular; D004926:Escherichia coli; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D011994:Recombinant Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D000535:Aluminum; D020558:GTP Phosphohydrolases; D016283:Proto-Oncogene Proteins p21(ras); D008274:Magnesium