Biochemistry of COMT

COMT catalyzes the transfer of active methyl from S-adenosylmethionine (SAM) to dopamine and other catechols (Axelrod & Tomchick1958). The methylation is preferentially directed to the p-hydroxyl group of most substrates. In the brain, the enzyme exists in two distinct molecular forms: a soluble form with low affinity for catecholamine substrates, and a membrane-bound form with μM affinity with respect to dopamine (Jeffery & Roth 1984). The membrane-bound form can be solubilized with strong detergent, suggesting that it is an integral membrane protein. The activity of both forms is dependent on the presence of Mg2+, and is maximal at pH greater than 7. Mechanistic studies of the membrane-bound form suggest that catalysis is initiated with binding of the co-substrate SAM, followed by the formation of a ternary complex with dopamine. The reaction is inhibited by low concentrations of the end-product S-adenosylhomocysteine (Rivett & Roth 1982). Some biochemical properties of COMT are summarized in Table 6.1.

The membrane-bound form of COMT differs from the soluble form in having an extra 50-residue hydrophobic sequence at the N-terminus (Ulmanen et al. 1997). When expressed in transfected mammalian cells, the membrane-bound COMT is associated with the endoplasmic reticulum and nuclear membranes, but not in the plasma membrane – an indication that its substrates must be present in the cytosol rather than on the external plasma membrane, as was once believed.