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Interactions of the neurotoxin MPTP and its demethylated derivative (PTP) with monoamine oxidase-B
1Department of Biochemistry, Trinity College, Dublin, Ireland.
Abstract:
The kinetics of the interactions of MPTP and its N-des-methyl-derivative (PTP) have been studied. Both were mechanism-based inhibitors as well as substrates for the enzyme. Analysis of the reaction progress-curves for the formation of the corresponding dihydropyridine derivatives allowed the kinetic parameters for the process and the partition ratio, which corresponds to the number of mol. of product formed per mol. of enzyme inactivated, to be determined for both compounds. The conversion of MPTP to its corresponding pyridinium-ion derivative through the action of MAO-B is known to be essential for its neurotoxicity. PTP has been reported not to be neurotoxic, although it appears to be a relatively good substrate for MAO-B as well as acting as a mechanism-based inhibitor. Studies of the changes in absorbance spectra during the MAO-B catalysed oxidation were consistent with the formation of the corresponding pyridinium-ion derivative (MPP+), which is known to be the effective neurotoxin, as the end-product when MPTP was oxidized. In contrast the oxidation of PTP appeared to stop at the dihydropyridine stage with no significant further oxidation to the corresponding pyridine-derivative.
Insights
MPTP is converted to a neurotoxic pyridinium ion by MAO-B, while its derivative PTP stops at an intermediate stage. This difference explains why MPTP is toxic and PTP is not.
Area of Science:
- Biochemistry
- Neuroscience
- Enzyme kinetics
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a known neurotoxin.
- MPTP's neurotoxicity is mediated by its conversion to MPP+ (1-methyl-4-phenylpyridinium ion).
- PTP (1-phenyl-1,2,3,6-tetrahydropyridine) is structurally similar to MPTP but lacks reported neurotoxicity.
Purpose of the Study:
- To investigate the kinetic mechanisms of MPTP and PTP interactions with monoamine oxidase B (MAO-B).
- To elucidate the biochemical differences underlying the neurotoxicity of MPTP versus the non-neurotoxicity of PTP.
- To determine kinetic parameters and partition ratios for MPTP and PTP as MAO-B substrates and inhibitors.
Main Methods:
- Kinetic analysis of reaction progress curves for MPTP and PTP oxidation by MAO-B.
- Determination of kinetic parameters, including partition ratios, for enzyme inactivation.
- Spectrophotometric monitoring of absorbance changes during MAO-B catalyzed oxidation.
Main Results:
- Both MPTP and PTP function as mechanism-based inhibitors and substrates for MAO-B.
- MPTP oxidation by MAO-B yields the pyridinium ion (MPP+), consistent with its known neurotoxic pathway.
- PTP oxidation by MAO-B appears to terminate at the dihydropyridine intermediate, without significant conversion to the pyridine derivative.
Conclusions:
- The distinct metabolic fates of MPTP and PTP under MAO-B catalysis explain their differential neurotoxicity.
- The complete oxidation of MPTP to MPP+ is crucial for its neurotoxic effects.
- PTP's inability to be fully oxidized to its corresponding pyridine derivative by MAO-B accounts for its lack of neurotoxicity.