A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain

Abstract

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.