|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 .
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
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>) . 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
In addition to the FAD-binding domain, all of the FR family members
have an NAD(P)H-binding domain.
May 2008 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|FAD_FR, PS51384; Ferredoxin reductase-type FAD binding domain profile (MATRIX)
|Sequences known to belong to this class detected by the profile:
|Other sequence(s) detected in Swiss-Prot:
|Matching PDB structures:
1A8P 1AMO 1B2R 1BJK ... [ALL]
||Curr. Opin. Struct. Biol. 1:954-967(1991).
||Fraaije M.W., Mattevi A.
||Flavoenzymes: diverse catalysts with recurrent features.
||Trends Biochem. Sci. 25:126-132(2000).
||To be or not to be an oxidase: challenging the oxygen reactivity of flavoenzymes.
||Trends Biochem. Sci. 31:276-283(2006).
||Dym O., Eisenberg D.
||Sequence-structure analysis of FAD-containing proteins.
||Protein Sci. 10:1712-1728(2001).
||Sridhar Prasad G., Kresge N., Muhlberg A.B., Shaw A., Jung Y.S., Burgess B.K., Stout C.D.
||The crystal structure of NADPH:ferredoxin reductase from Azotobacter vinelandii.
||Protein Sci. 7:2541-2549(1998).
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