Light D R, Waxman D J, Walsh C
Biochemistry. 1982 May 11;21(10):2490-8. doi: 10.1021/bi00539a031.
The stereochemical outcome of oxygen transfer to the sulfur moiety of aryl alkyl sulfides catalyzed by two flavoenzyme monooxygenases has been determined by resolution of sulfoxide product enantionmers on a high-pressure liquid chromatography column [Pirkle, W. H., Finn, J. M. Schreiner, J. L., & Hamper, B. C. (1981) J. Am. Chem. Soc. 103, 3964-3966] containing a 3,5-dinitrobenzoyl-D-phenylglycine chiral stationary phase. With 4-tolyl ethyl sulfide as substrate, cyclohexanone monooxygenase from Acinetobacter produces predominantly the (S)-(-)-sulfoxide (82% S, 18% R), a modest enantioselectivity. In contrast, the flavin adenine dinucleotide (FAD) containing a monooxygenase purified from hog liver microsomes carries out sulfoxidation to yield the (R)-(+)-sulfoxide enantiomer as major product (95% R, 5% S). The presence of the minor sulfoxide enantiomer in each case appears to be due to incomplete chiral processing by each enzyme and not to a competing, achiral, nonenzymic sulfoxidation process. The mammalian FAD-containing monooxygenase also oxygenates the divalent sulfur of the antiarthritic drug sulindac sulfide to yield a single dextrorotatory isomer of the sulfoxide prodrug. Analysis of the chiral outcome of sulfoxidation catalyzed by rat liver microsomes indicated that phenobarbital treatment increases the capacity for S-(-)-oxygenation of 4-tolyl ethyl sulfide, suggesting that the phenobarbital-induced cytochrome P-450 isoenzymes catalyze formation of the (S)-(-)-sulfoxide preferentially, a surmise validated in the following paper [Waxman, D. J., Light, D. R., & Walsh, C. (1982) Biochemistry (following paper in this issue)]. With sulindac sulfide as substrate, though, both control and phenobarbital-induced microsomes catalyze sulfoxidation to yield the same (+)-sulfoxide enantiomer generated by the purified FAD-containing monoxygenase, suggesting a low degree of participation by the cytochrome P-450 isozymes in sulfoxidation of this compound.
通过在装有3,5-二硝基苯甲酰基-D-苯基甘氨酸手性固定相的高压液相色谱柱上拆分亚砜产物对映体，确定了两种黄素酶单加氧酶催化氧转移至芳基烷基硫醚硫部分的立体化学结果[皮尔克，W.H.，芬恩，J.M.，施赖纳，J.L.，& 汉珀，B.C.（1981年）《美国化学会志》103, 3964 - 3966]。以4-甲苯基乙基硫醚为底物时，不动杆菌属的环己酮单加氧酶主要生成（S）-（-）-亚砜（82% S，18% R），对映选择性一般。相比之下，从猪肝微粒体中纯化得到的含黄素腺嘌呤二核苷酸（FAD）的单加氧酶进行硫氧化反应，生成（R）-（+）-亚砜对映体作为主要产物（95% R，5% S）。在每种情况下，次要亚砜对映体的存在似乎是由于每种酶的手性处理不完全，而非竞争性的、非手性的非酶硫氧化过程所致。含哺乳动物FAD的单加氧酶还将抗关节炎药物舒林酸硫化物的二价硫氧化，生成亚砜前药的单一右旋异构体。对大鼠肝微粒体催化硫氧化的手性结果分析表明，苯巴比妥处理增加了4-甲苯基乙基硫醚的S-（-）-氧化能力，这表明苯巴比妥诱导的细胞色素P-450同工酶优先催化（S）-（-）-亚砜的形成，这一推测在后续论文[韦克斯曼，D.J.，莱特，D.R.，& 沃尔什，C.（1982年）《生物化学》（本期后续论文）]中得到证实。然而，以舒林酸硫化物为底物时，对照和苯巴比妥诱导的微粒体都催化硫氧化，生成与纯化的含FAD单加氧酶产生的相同（+）-亚砜对映体这表明细胞色素P-450同工酶在该化合物硫氧化中的参与程度较低。
