Studies on the chirality of sulfoxidation catalyzed by bacterial flavoenzyme cyclohexanone monooxygenase and hog liver flavin adenine dinucleotide containing monooxygenase.

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.