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.
• NADPH:sulphite reductases.
• nitric oxide synthases.
• phthalate dioxygenase reductase.
• and various other flavoproteins.

NADH:cytochrome b5 reductase (CBR) serves as electron donor for cytochrome b5, a ubiquitous electron carrier (see IPR001199), thus participating in a variety of metabolic pathways (including steroid biosynthesis, desaturation and elongation of fatty acids, P450-dependent reactions, methaemoglobin reduction, etc.). A membrane-bound form of CBR is located on the cytosolic side of the endoplasmic reticulum, while a soluble form is found in erythrocytes [5]. In the membrane-bound form, the N-terminal residue is myristoylated [5]. Deficiency of the erythrocyte form causes hereditary methaemoglobinemia [6].

In biological nitrate assimilation, reduction of nitrate to nitrite is catalysed by the multidomain redox enzyme NAD(P)H:nitrate reductase (NR). Three forms of NR are known: an NADH-specific enzyme found in higher plants and algae (1.7.1.1); an NAD(P)H-bispecific enzyme found in higher plants, algae and fungi (1.7.1.2); and an NADPH-specific enzyme found only in fungi (1.7.1.3) [7]. NR can be divided into 3 structure/function domains: the molybdopterin cofactor binds in the N-terminal domain; the central region is the cytochrome b domain, which is similar to animal cytochrome b5 (see IPR001199); and the C-terminal portion of the protein is occupied by the FAD/NAD(P)H binding domain, which is similar to CBR [7]. The catalytic reduction of nitrate to nitrite can be viewed as a single polypeptide electron transport chain with electron flow from NAD(P)H -> FAD -> cytochrome b5 -> molybdopterin -> NO(3). Thus, the flavin domain of NR is functionally identical to CBR.

To date, the 3D-structures of the flavoprotein domain of Zea mays (Maize) nitrate reductase [7] and of Sus scrofa (Pig) NADH:cytochrome b5 reductase [8] have been solved. The overall fold is similar to that of ferredoxin:NADP⁺ reductase [9]: 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 flanked by 2 helices on each side).

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. Structural comparison of bovine erythrocyte, brain, and liver NADH-cytochrome b5 reductase by HPLC mapping. J. Biochem. 101, 1147-59
5. Identification of the NH2-terminal blocking group of NADH-cytochrome b5 reductase as myristic acid and the complete amino acid sequence of the membrane-binding domain. J. Biol. Chem. 259, 13349-54
6. Structural analysis of NADH-cytochrome b5 reductase in relation to hereditary methemoglobinemia. Prog. Clin. Biol. Res. 319, 107-19; discussion 120-1
7. 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
8. Crystal structure of NADH-cytochrome b5 reductase from pig liver at 2.4 A resolution. Biochemistry 34, 2763-7

Flavoprotein pyridine nucleotide cytochrome reductases [1] (FPNCR) ca
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