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
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