InterPro domain: IPR001709

Flavoprotein pyridine nucleotide cytochrome reductases [ 1 ] (FPNCR) catalyse the interchange of reducing equivalents between one-electron carriers and the two-electron-carrying nicotinamide dinucleotides. The enzymes include ferredoxin:NADP ⁺ reductases (FNR) [ 2 ], plant and fungal NAD(P)H:nitrate reductases [ 3 , 3 ], NADH:cytochrome b5 reductases [ 4 ], NADPH:P450 reductases [ 5 ], NADPH:sulphite reductases [ 6 ], nitric oxide synthases [ 7 ], phthalate dioxygenase reductase [ 8 ], and various other flavoproteins.

Despite functional similarities, FPNCRs show no sequence similarity to NADPH:adrenodoxin reductases [ 9 ], nor to bacterial ferredoxin:NAD ⁺ reductases and their homologues [ 10 ]. To date, 3D-structures of 4 members of the family have been solved: Spinacia oleracea (Spinach) ferredoxin:NADP ⁺ reductase [ 11 ]; Burkholderia cepacia (Pseudomonas cepacia) phthalate dioxygenase reductase [ 12 ]; the flavoprotein domain of Zea mays (Maize) nitrate reductase [ 12 ]; and Sus scrofa (Pig) NADH:cytochrome b5 reductase [ 13 ]. In all of them, the FAD-binding domain (N-terminal) has the topology of an anti-parallel beta-barrel, while the NAD(P)-binding domain (C-terminal) has the topology of a classical pyridine dinucleotide-binding fold (i.e. a central parallel beta-sheet with 2 helices on each side) [ 14 ]. In spite of such structural similarities, the level of amino acid identity between family members is at or below the limit of significance (e.g., nitrate reductase is only 15% identical to FNR) [ 14 ].

1. The sequence of squash NADH:nitrate reductase and its relationship to the sequences of other flavoprotein oxidoreductases. A family of flavoprotein pyridine nucleotide cytochrome reductases. J. Biol. Chem. 266, 23542-7
2. Structure-function relations for ferredoxin reductase. J. Bioenerg. Biomembr. 26, 89-99
3. Functional domains of assimilatory nitrate reductases and nitrite reductases. Trends Biochem. Sci. 15, 315-9
4. Complete amino acid sequence of NADH-cytochrome b5 reductase purified from human erythrocytes. J. Biochem. 99, 407-22
5. An unusual yet strongly conserved flavoprotein reductase in bacteria and mammals. Trends Biochem. Sci. 16, 154-8
6. Characterization of the flavoprotein moieties of NADPH-sulfite reductase from Salmonella typhimurium and Escherichia coli. Physicochemical and catalytic properties, amino acid sequence deduced from DNA sequence of cysJ, and comparison with NADPH-cytochrome P-450 reductase. J. Biol. Chem. 264, 15796-808
7. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351, 714-8
8. Structural prototypes for an extended family of flavoprotein reductases: comparison of phthalate dioxygenase reductase with ferredoxin reductase and ferredoxin. Protein Sci. 2, 2112-33
9. cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases. Eur. J. Biochem. 180, 479-84
10. Rubredoxin reductase of Pseudomonas oleovorans. Structural relationship to other flavoprotein oxidoreductases based on one NAD and two FAD fingerprints. J. Mol. Biol. 212, 135-42
11. Atomic structure of ferredoxin-NADP+ reductase: prototype for a structurally novel flavoenzyme family. Science 251, 60-6
12. Crystal structure of the FAD-containing fragment of corn nitrate reductase at 2.5 A resolution: relationship to other flavoprotein reductases. Structure 2, 809-21
13. Specific arrangement of three amino acid residues for flavin-binding barrel structures in NADH-cytochrome b5 reductase and the other flavin-dependent reductases. FEBS Lett. 361, 97-100