SUBSTRATE SPECIFICITIES OF RABBIT LUNG AND PORCINE LIVER FLAVIN-CONTAINING MONOOXYGENASES - DIFFERENCES DUE TO SUBSTRATE SIZE
SUBSTRATE SPECIFICITIES OF RABBIT LUNG AND PORCINE LIVER FLAVIN-CONTAINING MONOOXYGENASES - DIFFERENCES DUE TO SUBSTRATE SIZE
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DOI：
10.1021/tx00016a016
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发表时间：
1990-07-01
影响因子：
4.1
通讯作者：
ZIEGLER, DM
中科院分区：
文献类型：
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作者：
NAGATA, T;WILLIAMS, DE;ZIEGLER, DM
用纯化的兔肺和猪肝含黄素单加氧酶（FMO）检测了吩噻嗪、2-（三氟甲基）吩噻嗪和一系列烷基侧链长度从C2到C7不等的10-（N，N-二甲基氨基烷基）-2-（三氟甲基）吩噻嗪的底物活性。虽然所有的底物肝FMO，只有吩噻嗪轴承C6和C7的烷基侧链被氧化在显着的速度由肺FMO。从硫脲，苯基硫脲，和萘基硫脲的氧化反应速度计算的动力学常数表明，亲核杂原子上的一个分子的末端不大于六元环的横截面被两种酶氧化，但除了庞大的亲脂性取代基增加的Km的N-取代硫脲兔肺FMO和1，3-二苯基硫脲（thiocarbanilide）被完全排除。从排除的化合物和氧化的化合物的尺寸来看，似乎兔肺FMO中的过氧化氢黄素约为6-8埃。在不大于8埃的通道中的表面下。在其最长轴上的直径。在肝FMO中导致这种氧化剂的通道似乎更开放，并且容易接纳具有三环环的化合物。底物通道尺寸的差异似乎是肝和肺FMO之间底物特异性差异的原因。
Phenothiazine, 2-(trifluoromethyl)phenothiazine, and a series of 10-(N,N-dimethylaminoalkyl)-2-(trifluoromethyl)phenothiazines with alkyl side chains varying in length from C2 to C7 were tested for substrate activity with purified rabbit lung and porcine liver flavin-containing monooxygenases (FMO). While all were substrates for the hepatic FMO, only phenothiazines bearing C6 and C7 alkyl side chains were oxidized at significant rates by the pulmonary FMO. Kinetic constants calculated from reaction velocities for the oxidation of thiourea, phenylthiourea, and naphthylthiourea indicate that a nucleophilic heteroatom on the end of a molecule not much larger than a six-membered ring in cross section is oxidized by both enzymes, but the addition of bulky lipophilic substituents increases the Km of N-substituted thioureas for rabbit lung FMO and 1,3-diphenylthiourea (thiocarbanilide) is excluded entirely. From the dimensions of compounds excluded and from those oxidized, it would appear that the hydroperoxyflavin in rabbit lung FMO lies about 6-8 .ANG. below the surface in a channel no more than 8 .ANG. in diameter in its longest axis. The channel leading to this oxidant in hepatic FMO appears more open and readily admits compounds bearing a tricyclic ring. Differences in dimensions of the substrate channel appear responsible for some of the differences in substrate specificities between liver and lung FMO.