Irreversible inhibition of aromatic- l-amino acid decarboxylase by α-difluoromethyl-DOPA and metabolism of the inhibitor

Abstract

In vitro, α-difluoromethyl DOPA (DFMD, RMI 71801), at concentrations from 2 to 20 μM, inhibits aromatic- L-amino acid decarboxylase (AADC) in a time-dependent manner. After inhibition, the activity of the enzyme cannot be restored by dialysis. The inhibition is prevented by addition of an excess of the substrate l-DOPA. Near to one mole of ring-tritiated DFMD binds to one mole of enzyme during the inhibition process. The absorption spectrum of AADC is slightly modified by DFMD. No transformation product of the inhibitor is accumulated during incubation with the enzyme. It is concluded that DFMD is an enzyme-activated inhibitor of AADC. In vitro and in vivo, DFMD is a substrate of catechol O-methyltransferase.