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PROSITE documentation PDOC51384

Ferredoxin reductase-type FAD-binding domain profile


Flavoenzymes have the ability to catalyse a wide range of biochemical reactions. They are involved in the dehydrogenation of a variety of metabolites, in electron transfer from and to redox centres, in light emission, in the activation of oxygen for oxidation and hydroxylation reactions [1,2]. About 1% of all eukaryotic and prokaryotic proteins are predicted to encode a flavin adenine dinucleotide (FAD)-binding domain [3]. According to structural similarities and conserved sequence motifs, FAD-binding domains have been grouped in three main families: (i) the ferredoxin reductase (FR)-type FAD-binding domain, (ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the PCMH-type FAD-binding domain [4].

The FAD cofactor consists of adenosine monophosphate (AMP) linked to flavin mononucleotide (FMN) by a pyrophosphate bond. The AMP moiety is composed of the adenine ring bonded to a ribose that is linked to a phosphate group. The FMN moiety is composed of the isoalloxazine-flavin ring linked to a ribitol, which is connected to a phosphate group. The flavin functions mainly in a redox capacity, being able to take up two electrons from one substrate and release them two at a time to a substrate or coenzyme, or one at a time to an electron acceptor. The catalytic function of the FAD is concentrated in the isoalloxazine ring, whereas the ribityl phosphate and the AMP moiety mainly stabilize cofactor binding to protein residues [1,2].

The structural core of all FR family members is well conserved. The FAD-binding fold characteristic of the FR family is a cylindrical β-domain with a flattened six-stranded antiparallel β-barrel organized into two orthogonal sheets (B1-B2-B5 and B4-B3-B6) separated by one α-helix (see for example <PDB:IA8P>) [5]. The cylinder is open between strands B4 and B5 which makes space for the isoalloxazine and ribityl moieties of the FAD. One end of the cylinder is covered by the only helix of the domain, which is essential for the binding of the pyrophosphate groups of the FAD. The FR family contains two conserved motifs, one (R-x-Y-[ST]) located in B4 where the invariant positively charge Arg residue forms hydrogen bonds to the negative pyrophosphate oxygen atom. The other conserved sequence motif is G-x(2)-[ST]-x(2)-L-x(5)-G-x(7)-P-x-G, which is part of H1-B6 and is known as the phosphate-binding motif [4,5].

Some proteins known to contain a FR-type FAD-binding domain are listed below:

  • Eukaryotic NADH-cytochrome b5 reductase. It is a membrane-bound hemoprotein which acts as an electron carrier for several membrane-bound oxygenases.
  • Eukaryotic NADPH-cytochrome P450 reductase. This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome b5.
  • Nitrate reductase. It is a key enzyme involved in the first step of nitrate assimilation in plants, fungi and bacteria.
  • Bacterial ferredoxin reductase. It transports electrons between flavodoxin or ferredoxin and NADPH. It is involved in the reductive activation of cobalamin-independent methionine synthase, pyruvate formate lyase and anaerobic ribonucleotide reductase.
  • Bacterial flavohemoprotein. It is involved in nitric oxide detoxification in an aerobic process, termed nitric oxide dioxygenase (NOD) reaction.
  • Bacterial Na(+)-translocating NADH-quinone reductase (NQR) subunit F. NQR complex catalyzes the reduction of ubiquinone-1 to ubiquinol by two successive reactions, coupled with the transport of Na(+) ions from the cytoplasm to the periplasm.

The profile we developed covers the whole ferredoxin reductase type FAD-binding domain.


In addition to the FAD-binding domain, all of the FR family members have an NAD(P)H-binding domain.

Last update:

May 2008 / First entry.

Technical section

PROSITE method (with tools and information) covered by this documentation:

FAD_FR, PS51384; Ferredoxin reductase-type FAD binding domain profile  (MATRIX)


1AuthorsMathews F.S.
TitleNew flavoenzymes.
SourceCurr. Opin. Struct. Biol. 1:954-967(1991).

2AuthorsFraaije M.W., Mattevi A.
TitleFlavoenzymes: diverse catalysts with recurrent features.
SourceTrends Biochem. Sci. 25:126-132(2000).
PubMed ID10694883

3AuthorsMattevi A.
TitleTo be or not to be an oxidase: challenging the oxygen reactivity of flavoenzymes.
SourceTrends Biochem. Sci. 31:276-283(2006).
PubMed ID16600599

4AuthorsDym O., Eisenberg D.
TitleSequence-structure analysis of FAD-containing proteins.
SourceProtein Sci. 10:1712-1728(2001).
PubMed ID11514662

5AuthorsSridhar Prasad G., Kresge N., Muhlberg A.B., Shaw A., Jung Y.S., Burgess B.K., Stout C.D.
TitleThe crystal structure of NADPH:ferredoxin reductase from Azotobacter vinelandii.
SourceProtein Sci. 7:2541-2549(1998).
PubMed ID9865948

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