Inactivation of 3-(3,4-dihydroxyphenyl)alanine decarboxylase by 2-(fluoromethyl)-3-(3,4-dihydroxyphenyl)alanine.
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 carbon and fluoride from I and results in the stoichimetric formation of a covalent enzyme-inhibitor adduct. The data are consistent with I being a suicide inactivator of the enzyme, and a plausible mechanism for the inactivation process is presented. The inactivation is highly efficient in that 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 also a potent inactivator of the enzyme. In vivo compound I is found to inactivate both brain and peripheral (liver) Dopa decarboxylase activity. The possible significance of these data with respect to the known antihypertensive effect of I is discussed.
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001921:Brain / Q000201:enzymology; D002250:Carbon Radioisotopes; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008750:Methyldopa / Q000031:analogs & derivatives*; D051381:Rats; D013379:Substrate Specificity; D013552:Swine; D014316:Tritium
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002250:Carbon Radioisotopes; D014316:Tritium; D008750:Methyldopa; C019494:alpha-monofluoromethyldopa; D000409:Alanine