Molecular pharmacology of adipocyte-secreted autotaxin

Autotaxin is a type II ecto-nucleotide pyrophosphate phosphodiesterase enzyme. It has been recently discovered that autotaxin also catalyses a lyso-phospholipase D activity. This enzyme probably provides most of the extracellular lyso-phosphaticlic acid from lyso-phosphatidylcholine. There is almost no pharmacological tools available to study autotaxin. Indeed, all the reponed inhibitors, thus far, are uneasy-to-use, lyso-phosphaticlic acid derivatives. Initially, autotaxin was recognized as a phosphodiesterase (NPP2) [Bollen et al., Curt. Rev. Biochem. Biol. 35 (2000) 393-432], based on sequence similarity and enzymatic capability of autotaxin to catalyse ecto-nucleoticlase activity. Phosphodiesterase forms a large family of enzymes characterized by a large number of chemically diverse inhibitors. None of them have been tested on autotaxin activity. For this reason, we screened those reported inhibitors, as well as a series of compounds, mostly kinase inhibitor-oriented, on autotaxin activity. Only two compounds of the various phosphodiesterase inhibitors (calmidazolium and vinpocetine) were potent enough to inhibit autotaxin catalytic activity. From the kinase inhibitor library, we found damnacanthal and hypericin, inhibiting phosphodiesterase activity in the 100-mu M range, comparable to most of other available phospholipid-like inhibitors. (C) 2008 Elsevier Ireland Ltd. All rights reserved.