A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain.
Although the principal effect of paclitaxel (taxol) is in preventing depolymerization of microtubules, other effects have been described recently. In the present manuscript, we demonstrate an inhibitory effect on the enzyme peptidylarginine deiminase (PAD) which converts peptidyl bound arginine to citrulline. To study the mechanism of action of the drug on PAD, a number of studies were carried out with purified enzyme. With the synthetic substrate benzoyl-arginine ethyl ester (BAEE), almost total inhibition of activity was observed at 12. 5 mM. With myelin basic protein (MBP) as a substrate, deimination of arginyl residues was prevented by 0.5 mM paclitaxel. The velocity-substrate curve was unusual since substrate enhancement was observed at 5 mM BAEE. These data suggested the presence of two binding sites on the enzyme. Inhibition of activity by paclitaxel was non-competitive for both sites.
Division of Structural Biology and Biochemistry, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
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Pritzker
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Moscarello
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
D004791:Enzyme Inhibitors; D004676:Myelin Basic Protein; D001120:Arginine; C009727:benzoylarginine ethyl ester; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D017239:Paclitaxel