TY - JOUR
T1 - Deuterium isotope effects for the oxidation of 1-methyl-3-phenyl-3-pyrrolinyl analogues by monoamine oxidase B
AU - Pretorius, Anél
AU - Ogunrombi, Modupe O.
AU - Terre'Blanche, Gisella
AU - Castagnoli, Neal
AU - Bergh, Jacobus J.
AU - Petzer, Jacobus P.
N1 - Funding Information:
We are grateful to Jan du Preez and the staff of the Analytical Technology Laboratory, North-West University for their support. The NMR and MS spectra were recorded by André Joubert, Johan Jordaan, and Louis Fourie of the SASOL Centre for Chemistry, North-West University. This work was supported by grants from the National Research Foundation and the Medical Research Council, South Africa.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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 α-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 Vmax and Vmax/Km 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-d5 analogues as the deuterated substrates. The apparent isotope effects for the two substrates were 4.29 and 3.98 on Vmax, while the isotope effects on Vmax/Km 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-d2, as deuterated substrate, are D(Vmax) = 3.55; D(Vmax/Km) = 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.
AB - 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 α-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 Vmax and Vmax/Km 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-d5 analogues as the deuterated substrates. The apparent isotope effects for the two substrates were 4.29 and 3.98 on Vmax, while the isotope effects on Vmax/Km 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-d2, as deuterated substrate, are D(Vmax) = 3.55; D(Vmax/Km) = 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.
KW - 1-Methyl-3-phenyl-3-pyrroline
KW - Kinetic isotope effect
KW - MPTP
KW - Monoamine oxidase B
UR - http://www.scopus.com/inward/record.url?scp=52949110956&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2008.09.001
DO - 10.1016/j.bmc.2008.09.001
M3 - Article
C2 - 18799315
AN - SCOPUS:52949110956
SN - 0968-0896
VL - 16
SP - 8813
EP - 8817
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 19
ER -