Inactivation of 3-(3,4-dihydroxyphenyl)alanine decarboxylase by 2-(fluoromethyl)-3-(3,4-dihydroxyphenyl)alanine

Abstract

2-(Fluoromethyl)-3-(3,4-dihydroxyphenyl)alanine [.alpha.-FM-dopa (I)] causes rapid, time-dependent, stereospecific and irreversible inhibition of hog kidney aromatic amino acid (dopa) decarboxylase. The inactivation occurs with loss of both the carboxyl C and fluoride from I and results in the stoichiometric formation of a covalent enzyme-inhibitor adduct. I may be a suicide inactivator of the enzyme and a plausible mechanism for the inactivation process is presented. The inactivation is highly efficient: there is essentially no enzymatic turnover of I to produce the corresponding amine, 1-(fluoromethyl)-2-(3,4-dihydroxyphenyl)ethylamine [.alpha.-FM-dopamine (II)]. Amine II is a potent inactivator of the enzyme. In vivo in rats compound I inactivates both brain and peripheral (liver) dopa decarboxylase activity. The possible significance of the data with respect to the known antihypertensive effect of I is discussed.