An essential cysteine (Cys-227) in human carbonyl reductase is involved in glutathione binding.

Abstract

Cytosolic carbonyl reductase (secondary-alcohol:NADP+ oxidoreductase, EC 1.1.1.184) is a monomeric member of the short-chain dehydrogenase/reductase superfamily (Wermuth, 1992). It catalyzes the NADPH-dependent reduction of a variety of endogenous and xenobiotic carbonyl compounds, including prostaglandins, steroids and pterins as well as many quinones derived from polycyclic aromatic hydrocarbons and the anthracycline antibiotic daunorubicin (Ahmed et al., 1978; Wermuth, 1981; Jarabak et al., 1983; Nakayama et al., 1985; Park et al., 1991). Its natural substrate(s) and physiological role, however, are not known. Evidence from various studies suggests that glutathione (GSH) may act as a cofactor or modulator of enzyme activity and specificity. Cagen and Pisano (1979) first showed that prostaglandin A1, which by itself is not a substrate, is efficiently metabolized in the form of its GSH adduct by prostaglandin 9-keto reductase (identical to carbonyl reductase) from chicken heart and suggested that the natural substrates of the enzyme may be the GSH conjugates of carbonyl compounds. A similar preference for the GSH adduct of prostaglandin A1 was subsequently demonstrated for carbonyl reductase from various mammalian sources (Toft and Hansen, 1979; Chang and Tai, 1981) including man (Wermuth, 1981; Feldman et al., 1981). More recently, the GSH adducts of several quinones of polycyclic aromatic hydrocarbons were found to be both substrates and inhibitors of human placental carbonyl reductase (Chung et al., 1987a). A specific GSH binding site close to, or overlapping with, the active site was postulated by Jarabak and coworkers based on the observation that oxidized glutathione (GSSG) and other oxidation products of GSH are potent inhibitors of carbonyl reductase from human placenta (Feldman et al., 1981; Chung et al., 1987b).