InterPro domain: IPR023753

FAD flavoproteins belonging to the family of pyridine nucleotide-disulphide oxidoreductases (glutathione reductase, trypanothione reductase, lipoamide dehydrogenase, mercuric reductase, thioredoxin reductase, alkyl hydroperoxide reductase) share sequence similarity with a number of other flavoprotein oxidoreductases, in particular with ferredoxin-NAD+ reductases involved in oxidative metabolism of a variety of hydrocarbons (rubredoxin reductase, putidaredoxin reductase, terpredoxin reductase, ferredoxin-NAD+ reductase components of benzene 1,2-dioxygenase, toluene 1,2-dioxygenase, chlorobenzene dioxygenase, biphenyl dioxygenase), NADH oxidase and NADH peroxidase [ 1 , 2 , 3 ]. Comparison of the crystal structures of human glutathione reductase and Escherichia coli thioredoxin reductase reveals different locations of their active sites, suggesting that the enzymes diverged from an ancestral FAD/NAD(P)H reductase and acquired their disulphide reductase activities independently [ 4 ].

Despite functional similarities, oxidoreductases of this family show no sequence similarity with adrenodoxin reductases [ 4 ] and flavoprotein pyridine nucleotide cytochrome reductases (FPNCR) [ 5 ]. Assuming that disulphide reductase activity emerged later, during divergent evolution, the family can be referred to as FAD-dependent pyridine nucleotide reductases, FADPNR.

To date, 3D structures of glutathione reductase [ 6 ], thioredoxin reductase [ 7 ], mercuric reductase [ 7 ], lipoamide dehydrogenase [ 8 ], trypanothione reductase [ 9 ] and NADH peroxidase [ 10 ] have been solved. The enzymes share similar tertiary structures based on a doubly-wound alpha/beta fold, but the relative orientations of their FAD- and NAD(P)H-binding domains may vary significantly. By contrast with the FPNCR family, the folds of the FAD- and NAD(P)H-binding domains are similar, suggesting that the domains evolved by gene duplication [ 11 ].

This entry describes the FAD binding domain which has a nested NADH binding domain and is found in both class I and class II oxidoreductases.

1. 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
2. Molecular cloning and analysis of the gene encoding the NADH oxidase from Streptococcus faecalis 10C1. Comparison with NADH peroxidase and the flavoprotein disulfide reductases. J. Mol. Biol. 227, 658-71
3. Convergent evolution of similar function in two structurally divergent enzymes. Nature 352, 172-4
4. cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases. Eur. J. Biochem. 180, 479-84
5. 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
6. Refined structure of glutathione reductase at 1.54 A resolution. J. Mol. Biol. 195, 701-29
7. Structure of the detoxification catalyst mercuric ion reductase from Bacillus sp. strain RC607. Nature 352, 168-72
8. Refined crystal structure of lipoamide dehydrogenase from Azotobacter vinelandii at 2.2 A resolution. A comparison with the structure of glutathione reductase. J. Mol. Biol. 220, 975-94
9. X-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution. Proc. Natl. Acad. Sci. U.S.A. 88, 8764-8
10. Structure of NADH peroxidase from Streptococcus faecalis 10C1 refined at 2.16 A resolution. J. Mol. Biol. 221, 1325-44
11. Gene duplication in glutathione reductase. J. Mol. Biol. 138, 335-47