Great adaptability of the heme-cysteinate monooxygenases family to very diverse substrates and sophisticated reactions

Abstract

Heme-cysteinate proteins, such as cytochromes P 450( CYPs ) and nitric oxide synthases (NOSs), catalyze the monooxygenation of a huge number of substrates with very diverse structures. The ability of CYPs to oxidize a myriad of xenobiotics, in order to facilitate their elimination, plays a key role in the adaptation of aerobic organisms to their always changing chemical environment. Moreover, some members of the CYP superfamily and the NOSs are involved in the biosynthesis of key biological endogenous molecules, such as estrogens or NO, through the catalysis of highly sophisticated and regulated reactions. How can proteins using the same catalytic heme-cysteinate cofactor and mechanism of dioxygen activation oxidize such diverse and always changing substrates and catalyze different, sometimes very sophisticated reactions? Recent data on the first X-ray structures of mammalian cytochrome P 450-substrate complexes and on the mechanism of NO-synthases has permitted an understanding of this"double adaptation" of heme-cysteinate monooxygenases towards very diverse substrates and different reactions. These data show that cytochromes P 450 involved in the metabolism of xenobiotics are able to oxidize very different substrates by offering a great choice of very diverse and malleable active sites. They also show that heme-cysteinate monooxygenases are able to catalyze special, sophisticated reactions, such as the selective oxidation of L-arginine to NO, by using supplementary cofactors adapted for the required catalysis.