Krueger M J, McKeown K, Ramsay R R, Youngster S K, Singer T P
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Biochem J. 1990 May 15;268(1):219-24. doi: 10.1042/bj2680219.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its primary oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), are mechanism-based inhibitors of monoamine oxidases A and B. The pseudo-first-order rate constants for inactivation were determined for various analogues of MPTP and MPDP+ and the concentrations in all redox states were measured throughout the reaction. Disproportionation was observed for all the dihydropyridiniums, but non-enzymic oxidation was insignificant. The dihydropyridiniums were poor substrates for monoamine oxidase A and, consequently, inactivated the enzyme only slowly, despite partition coefficients lower than those for the tetrahydropyridines. For monoamine oxidase B, the dihydropyridiniums were more effective inactivators than the tetrahydropyridines. Substitutions in the aromatic ring had no major effect on the inactivation of monoamine oxidase B, but the 2'-ethyl- and 3'-chloro-substituted compounds were very poor mechanism-based inactivators of monoamine oxidase A. It is clear that both oxidation steps can generate the reactive species responsible for inactivation.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）及其主要氧化产物1-甲基-4-苯基-2,3-二氢吡啶鎓（MPDP+）是基于机制的单胺氧化酶A和B的抑制剂。测定了MPTP和MPDP+各种类似物失活的伪一级速率常数，并在整个反应过程中测量了所有氧化还原状态下的浓度。观察到所有二氢吡啶鎓都发生了歧化反应，但非酶促氧化作用不显著。二氢吡啶鎓是单胺氧化酶A的不良底物，因此，尽管其分配系数低于四氢吡啶，但仅能缓慢地使该酶失活。对于单胺氧化酶B，二氢吡啶鎓比四氢吡啶更有效地使酶失活。芳环上的取代对单胺氧化酶B的失活没有重大影响，但2'-乙基和3'-氯取代的化合物是非常差的基于机制的单胺氧化酶A失活剂。显然，两个氧化步骤都能产生负责失活的活性物种。
