X-Ray Crystallography of Catechol O-Methyltransferase: Perspectives for Target-Based Drug Development

Abstract

Catechol O-methyltransferase (COMT) plays a role in the metabolism of catecholamines and some other substances containing the catechol structure. COMT also inactivates L-dopa, which is used as a drug in the treatment of Parkinson's disease. COMT catalyzes the transfer of the methyl group from the coenzyme S-adenosyl-L-methionine (AdoMet) to one of the phenolic hydroxyl groups of a catechol or substituted catechols. The presence of magnesium ions is required for the catalysis. The reaction products are O-methylated catechol and S-adenosyl-L-homocysteine (AdoHcy). COMT occurs in two forms, soluble and membrane-bound, the latter having a 50 amino-acids-long membrane anchor region. The membrane-bound COMT has about 10 times lower Km value than soluble COMT, but at saturating substrate concentrations, the catalytic number of both enzyme forms is similar. At low concentrations, catecholamines are methylated more efficiently by membrane-bound COMT. The active site of COMT consists of the AdoMet-binding domain and the catalytic site. The catalytic site is formed by a few amino acids that are important for substrate binding and catalysis of the methylation reaction, and by the metal ion. The Mg 2+ bound to the enzyme makes the hydroxyl groups of the catechol substrate more easily ionizable. In a vicinity of one hydroxyl from the bound substrate, there is a lysine residue, which accepts the proton of that moiety, and subsequently the methyl group is transferred from the AdoMet to the hydroxyl. The shallow groove in the active site of COMT allows the long side chains of inhibitors to reach the surface of the enzyme. The best inhibitors of COMT are nitrocatechols. Ionized molecules penetrate poorly the blood brain barrier. In clinical trials it has been shown that the beneficial effect on the L-dopa metabolism in the treatment of Parkinson's disease is reached with a peripheral COMT inhibitor such as entacapone.