Cashman J R, Olsen L D
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 94143-0446.
Mol Pharmacol. 1990 Oct;38(4):573-85.
The reaction of NalO4, highly purified flavin-containing monooxygenase (EC 1.14.13.8), and microsomes from hog liver with 2-aryl-1,3-dithiolanes and 2-aryl-1,3-dithiolane S-oxides was investigated. The initial rates determined for the microsome- and purified flavin-containing monooxygenase-catalyzed rate of S-oxidation of para-substituted 2-aryl-1,3-dithiolanes were similar, demonstrating that S-oxidation of these substrates occurred with similar velocities at saturating concentrations of substrate and, at least for the first S-oxidation, the reaction was insensitive to the nature of the para-substituent. The diastereoselectivity of S-oxygenation of 2-aryl-1,3-dithiolanes was determined and, in general, a marked preference for addition of oxygen to the sulfide sulfur atom was observed to occur trans to the aryl groups. In all cases examined, enantioselective enzymatic S-oxidation was observed. For S-oxide formation in microsomes, the data provided evidence for a minor role of cytochrome P-450 in S-oxide formation, but the flavin-containing monooxygenase was mainly responsible for production of S-oxide. In contrast to previous reports, the enantioselectivity of S-oxidation catalyzed by highly purified cytochrome P-450IIB-1 and cytochrome P-450IIB-10 was not always opposite to that catalyzed by hog liver flavin-containing monooxygenase activity. 2-Aryl-1,3-dithiolane S-oxides were also oxidized a second time by NalO4, microsomes, or highly purified flavin-containing monooxygenase from hog liver but not cytochrome P-450IIB-1 or P-450IIB-10. The rate of the second oxidation was 10-15-fold slower than the corresponding first S-oxidation and S,S'-dioxide formation was markedly dependent on the electronic nature of the para-substituent (Hammett correlation rho value of -1.3 and -1.1 for microsomes and highly purified flavin-containing monooxygenase from hog liver, respectively). The large dependence of the rate of S,S'-dioxide formation on the nature of the para-substituent demonstrates that velocity values at saturating concentrations of S-oxide were not the same for all 2-aryl-1,3-dithiolane S-oxides and suggests that the chemical nature of the 2-aryl-1,3-dithiolane S-oxide contributes to the rate-determining step of this enzymatic reaction.
研究了高纯度含黄素单加氧酶（EC 1.14.13.8）、高碘酸钠以及猪肝微粒体与2-芳基-1,3-二硫戊环和2-芳基-1,3-二硫戊环S-氧化物的反应。测定了微粒体和纯化的含黄素单加氧酶催化对取代的2-芳基-1,3-二硫戊环S-氧化反应的初始速率，二者相似，这表明在底物饱和浓度下，这些底物的S-氧化反应速率相似，并且至少对于第一次S-氧化反应，该反应对对位取代基的性质不敏感。测定了2-芳基-1,3-二硫戊环S-氧合反应的非对映选择性，一般来说，观察到氧明显优先加成到与芳基处于反式的硫醚硫原子上。在所有检测的情况下，均观察到对映选择性酶促S-氧化反应。对于微粒体中S-氧化物的形成，数据表明细胞色素P-450在S-氧化物形成中起次要作用，但含黄素单加氧酶是S-氧化物产生的主要原因。与先前的报道相反，高纯度细胞色素P-450IIB-1和细胞色素P-450IIB-10催化的S-氧化反应的对映选择性并不总是与猪肝含黄素单加氧酶活性催化的相反。2-芳基-1,3-二硫戊环S-氧化物也会被高碘酸钠、微粒体或猪肝的高纯度含黄素单加氧酶再次氧化，但不会被细胞色素P-450IIB-1或P-450IIB-10氧化。第二次氧化反应的速率比相应的第一次S-氧化反应慢10 - 15倍，并且S,S'-二氧化物的形成明显取决于对位取代基的电子性质（微粒体和猪肝高纯度含黄素单加氧酶的哈米特相关ρ值分别为-1.3和-1.1）。S,S'-二氧化物形成速率对对位取代基性质的强烈依赖性表明，对于所有2-芳基-1,3-二硫戊环S-氧化物，在S-氧化物饱和浓度下的速率值并不相同，这表明2-芳基-1,3-二硫戊环S-氧化物的化学性质对该酶促反应的速率决定步骤有影响。
