title: Deuterium isotope effects for the oxidation of 1-methyl-3-phenyl-3-pyrrolinyl analogues by monoamine oxidase B.
abstract: The parkinsonian inducing agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a cyclic tertiary allylamine exhibiting good monoamine oxidase B (MAO-B) substrate properties. MAO-B catalyzes the ring alpha-carbon 2-electron bioactivation of MPTP to yield the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP(+)). The corresponding 5-membered ring MPTP analogue, 1-methyl-3-phenyl-3-pyrroline, also undergoes MAO-B-catalyzed oxidation to give the 2-electron oxidation product, 1-methyl-3-phenylpyrrole. Here we report the kinetic deuterium isotope effects on V(max) and V(max)/K(m) for the steady-state oxidation of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4-fluorophenyl)-3-pyrroline by baboon liver MAO-B, using the corresponding pyrroline-2,2,4,5,5-d(5) analogues as the deuterated substrates. The apparent isotope effects for the two substrates were 4.29 and 3.98 on V(max), while the isotope effects on V(max)/K(m) were found to be 5.71 and 3.37, respectively. The values reported for the oxidation of MPTP by bovine liver MAO-B with MPTP-6,6-d(2), as deuterated substrate, are (D)(V(max))=3.55; (D)(V(max)/K(m))=8.01. We conclude that the mechanism of the MAO-B-catalyzed oxidation of pyrrolinyl substrates is similar to that of the tetrahydropyridinyl substrates and that a carbon-hydrogen bond cleavage step is, at least partially, rate determining.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Pretorius
authors.forename: Modupe O
authors.initials: MO
authors.lastname: Ogunrombi
authors.forename: Gisella
authors.initials: G
authors.lastname: Terre'blanche
authors.forename: Neal
authors.initials: N
authors.lastname: Castagnoli
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002417:Cattle; D003903:Deuterium / Q000737:chemistry*; D015259:Dopamine Agents / Q000378:metabolism*; D007553:Isotope Labeling; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010215:Papio; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000378:metabolism*
chemical_list: D015259:Dopamine Agents; D009498:Neurotoxins; D011758:Pyrroles; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003903:Deuterium; D008995:Monoamine Oxidase