Catechol-O-Methyltransferase in Parkinson’s Disease

The introduction of levodopa therapy for Parkinson’s disease (PD), initially by Birkmayer and colleagues in 1961 and Barbeau and colleagues in 1962, and in its ultimately successful form by Cotzias and colleagues in 1967, still represents the defining landmark in the treatment of PD (1–3). This dramatic advance was preceded by methodical basic laboratory research in the late 1950s and early 1960s, which formed a groundwork documenting the presence of striatal dopamine deficiency in PD (4–8) and paved the road for the application of this knowledge in the clinical arena. These developments took place against a broader backdrop in which both the role of catecholamines and their metabolic pathways in body and brain were being unraveled (9). As part of this panorama, Axelrod, in 1957, first suggested that one of the metabolic pathways for catecholamines might be via O-methylation (9–11), and in the same year Shaw and colleagues proposed that catechol-O-methyltransferase (COMT) might be important in the inactivation of dihydroxyphenylalanine (DOPA) and dopamine (12). By 1964 the metabolic pathways for DOPA and dopamine had been delineated and the involved enzymes identified. Aromatic amino acid decarboxylase (AAAD) and COMT were identified as being responsible for converting