Catechol O-Methyltransferase: Characterization of the Protein, Its Gene, and the Preclinical Pharmacology of COMT Inhibitors

Abstract

Publisher Summary Catechol O-methyltransferase (COMT) is an enzyme that catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to one of the phenolic group of the catechol substrate in the presence of Mg2+ and following a sequential ordered mechanism. High COMT activity is found in the liver, kidney, and gut wall. A single COMT gene codes two separate enzymes, the soluble(S-COMT) and membrane-bound (MB-COMT) forms. S-COMT contains 221 amino acids. MB-COMT has an additional amino terminal extension of 43 (rat) or 50 (human) amino acids. Synthesis of recombinant S-COMT in E. coli and MB-COMT in the insect cells using vectors has helped in clarifying the biochemistry, physiology, and pharmacology of COMT. MB-COMT is partially responsible of the termination of dopaminergic and noradrenergic synaptic neurotransmission. S-COMT is a high-capacity enzyme responsible for the elimination of biologically active or toxic, particularly exogenous catechols and some hydroxylated metabolites. Accordingly, MB-COMT is a dominating isoenzyme in the human brain. Second-generation COMT inhibitors are potent, selective, and orally active. The current COMT inhibitors have been divided into three groups—mainly peripherally acting nitrocatechol-type compounds, broad-spectrum nitrocatechols having activity both in the periphery and the brain; and atypical compounds and pyridine, some of which are not COMT inhibitors in vitro but may instead inhibit catechol O-methylation by some other mechanism. COMT inhibitors improve the brain entry of L-dopa and decrease 3-OMD formation in the peripheral tissues. COMT inhibitors should also decrease fluctuations of the dopamine formation. A summary of some preclinical evidence supporting the suggested use is given in this chapter. Noradrenaline and dopamine deficiency in the synaptic cleft depicts depression. The remedy of this deficit by the use of tricyclic uptake inhibitors and monoamine oxidase inhibitors has become an established therapy for depression. The COMT inhibitors reaching the brain would decrease the metabolism of noradrenaline and dopamine.