SUBSTRATE SPECIFICITIES OF RABBIT LUNG AND PORCINE LIVER FLAVIN-CONTAINING MONOOXYGENASES - DIFFERENCES DUE TO SUBSTRATE SIZE

被引:63
作者
NAGATA, T
WILLIAMS, DE
ZIEGLER, DM
机构
[1] UNIV TEXAS,CLAYTON FDN BIOCHEM INST,AUSTIN,TX 78712
[2] OREGON STATE UNIV,DEPT FOOD SCI & TECHNOL,CORVALLIS,OR 97331
[3] UNIV TEXAS,DEPT CHEM,AUSTIN,TX 78712
[4] OREGON STATE UNIV,TOXICOL PROGRAM,CORVALLIS,OR 97331
关键词
D O I
10.1021/tx00016a016
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 Å below the surface in a channel no more than 8 Å 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. © 1990, American Chemical Society. All rights reserved.
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页码:372 / 376
页数:5
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