Figure 1.

A) COMT methylation of substrates (1) to give meta (2) and para (3) products. B) mechanism of COMT‐catalyzed methylation of catechols using the cofactor S‐adenosyl‐l‐methionine (AdoMet). Coordination of Mg²⁺ by the catechol hydroxy groups lowers their pK _a values, thus aiding deprotonation of the hydroxy group closest to the AdoMet methyl group by K144. E199 appears to hydrogen bond with the other hydroxy group. The orientation of the R group in the active site determines whether the meta‐ or para‐hydroxy group is methylated.