TY - JOUR T1 - Molecular Mechanisms Controlling the Rate and Specificity of Catechol <em>O</em>-Methylation by Human Soluble Catechol <em>O</em>-Methyltransferase JF - Molecular Pharmacology JO - Mol Pharmacol SP - 393 LP - 402 DO - 10.1124/mol.59.2.393 VL - 59 IS - 2 AU - Pia Lautala AU - Ismo Ulmanen AU - Jyrki Taskinen Y1 - 2001/02/01 UR - http://molpharm.aspetjournals.org/content/59/2/393.abstract N2 - Molecular mechanisms determining the turn-over rate and specificity of catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The most important mechanism decreasing the turnover rate and increasing affinity was the electron withdrawing effect of substituents. Several other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in thel-DOPA treatment of Parkinson's disease, the COMT inhibitors entacapone and tolcapone were not methylated, whereas the DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than l-DOPA, the target of COMT inhibition. The structure-activity relationships found allow the prediction of reactivity, affinity, and specificity with useful accuracy for catechols with a wide range of structures and properties. The knowledge can be used in the evaluation of metabolic interactions of endogenous catechols, drugs and dietary catechols, and in the designing of drugs with the catechol pharmacophore. ER -