title: NADPH-cytochrome P450 oxidoreductase: prototypic member of the diflavin reductase family.
abstract: NADPH-cytochrome P450 oxidoreductase (CYPOR) and nitric oxide synthase (NOS), two members of the diflavin oxidoreductase family, are multi-domain enzymes containing distinct FAD and FMN domains connected by a flexible hinge. FAD accepts a hydride ion from NADPH, and reduced FAD donates electrons to FMN, which in turn transfers electrons to the heme center of cytochrome P450 or NOS oxygenase domain. Structural analysis of CYPOR, the prototype of this enzyme family, has revealed the exact nature of the domain arrangement and the role of residues involved in cofactor binding. Recent structural and biophysical studies of CYPOR have shown that the two flavin domains undergo large domain movements during catalysis. NOS isoforms contain additional regulatory elements within the reductase domain that control electron transfer through Ca(2+)-dependent calmodulin (CaM) binding. The recent crystal structure of an iNOS Ca(2+)/CaM-FMN construct, containing the FMN domain in complex with Ca(2+)/CaM, provided structural information on the linkage between the reductase and oxgenase domains of NOS, making it possible to model the holo iNOS structure. This review summarizes recent advances in our understanding of the dynamics of domain movements during CYPOR catalysis and the role of the NOS diflavin reductase domain in the regulation of NOS isozyme activities.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, WI, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iyanagi
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Xia
authors.forename: Jung-Ja P
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D005415:Flavins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D005415:Flavins; D019001:Nitric Oxide Synthase; D009251:NADPH-Ferrihemoprotein Reductase