1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates. The nigrostriatal toxicity is not due to MPTP itself but to one or more oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or ‘suicide’ process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme.
1. The biosynthetic origin of the amide substituent of N -(α-hydroxyethyl)lysergamide has been studied. 2. [1- 14 C]Acetate, [ 14 C]formate, [2- 14 C]mevalonic acid lactone, [2- 14 C]indole, dl -[3- 14 C]tryptophan, dl -[3- 14 C]serine, dl -[2- 14 C]alanine and [2- 14 C]pyruvate were efficiently incorporated into the alkaloid, but not dl -[1- 14 C]alanine or [1- 14 C]pyruvate. 3. Only the dl -[2- 14 C]alanine- and [2- 14 C]pyruvate-derived alkaloid contained appreciable radioactivity in the amide substituent. 4. l -[ 15 N]Alanine-derived alkaloid was shown to be specifically labelled in the amide nitrogen. However, l -[ 14 C, 15 N]alanine was found to be incorporated into the methylcarbinolamide substituent with an appreciable increase in the 15 N/ 14 C ratio, suggesting that alanine is not the direct precursor of this moiety.