3-pyrrolines are mechanism-based inactivators of the quinone-dependent amine oxidases but only substrates of the flavin-dependent amine oxidases
3-pyrrolines are mechanism-based inactivators of the quinone-dependent amine oxidases but only substrates of the flavin-dependent amine oxidases
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DOI：
10.1021/ja0205434
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发表时间：
2002-10-16
影响因子：
15
通讯作者：
Sayre, LM
中科院分区：
文献类型：
--
作者：
Lee, Y;Ling, KQ;Sayre, LM
我们先前报道了3-吡咯啉和3-苯基-3-吡咯啉影响来自牛血浆（BPAO）的含铜醌依赖性胺氧化酶的时间依赖性失活（Lee等人，J. Am. 1996，118，7241-7242）。醌辅因子模型研究表明，涉及化学计量营业额的一个稳定的吡咯辅助因子的机制。模型研究的全部细节沿着报道了3-芳基-3-吡咯啉（芳基=取代的苯基、1-萘基、2-萘基）家族对BPAO的抑制数据，其中4-甲氧基-3-硝基苯基类似物是最有效的。同时，母体3-苯基类似物是来自牛肝脏的黄素依赖性线粒体单胺氧化酶B的纯底物。对4-甲氧基-3-硝基苯类似物灭活的BPAO的光谱研究（包括共振拉曼）与2，4，5-三羟基苯丙氨酸醌（TPQ）辅因子的共价衍生化一致。一类化合物作为一种胺氧化酶家族的灭活剂和另一种胺氧化酶家族的纯底物的区别代表了开发哺乳动物含铜胺氧化酶的选择性抑制剂的独特原因。
We previously reported that 3-pyrroline and 3-phenyl-3-pyrroline effect a time-dependent inactivation of the copper-containing quinone-dependent amine oxidase from bovine plasma (BPAO) (Lee et al. J. Am. Chem. Soc. 1996, 118, 7241-7242). Quinone cofactor model studies suggested a mechanism involving stoichiometric turnover to a stable pyrrolylated cofactor. Full details of the model studies are now reported along with data on the inhibition of BPAO by a family of 3-aryl-3-pyrrolines (aryl = substituted phenyl, 1-naphthyl, 2-naphthyl), with the 4-methoxy-3-nitrophenyl analogue being the most potent. At the same time, the parent 3-phenyl analogue is a pure substrate for the flavin-dependent mitochondrial monoamine oxidase B from bovine liver. Spectroscopic studies (including resonance Raman) on BPAO inactivated by the 4-methoxy-3-nitrophenyl analogue are consistent with covalent derivatization of the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. The distinction of a class of compounds acting as an inactivator of one amine oxidase family and a pure substrate of another amine oxidase family represents a unique lead to the development of selective inhibitors of the mammalian copper-containing amine oxidases.